A rare, immunologically mediated, interstitial lung disease characterized by respiratory symptoms (cough, dyspnea) due to sensitization and subsequent hypersensitivity to environmental antigens. The disorder may be accompanied by systemic manifestations (weight loss, fatigue).

Summary:
Epidemiology
The estimated worldwide incidence of hypersensitivity pneumonitis (HP) is in the 1/125,000-143,000 range and is highly dependent on climatic, geographical, occupational and industrial factors. It has a higher incidence rate among pigeon breeders and farmers. The prevalence is 1/33,000-100,000 in the general population. A large number of acute cases and chronic cases related to mold probably go undiagnosed.
Clinical description
HP covers a very wide spectrum of clinical presentations with acute, subacute, and chronic forms. The disease can develop in any age group and the main clinical signs in all forms are cough, dyspnea, and fatigue. The manifestations overlap with a large number of other pulmonary disorders. HP is distinguished between fibrotic (always chronic) and non-fibrotic forms (mostly with acute or subacute manifestations). Acute manifestations, occurring a few hours after intense exposure (4-16 hours), may involve fever, headache, cough, dyspnea and myalgia. Chronic disease develops due to low level continual exposure over months to years manifesting with severe dyspnea, cough, clubbing, weight loss and hypoxemia, which may worsen gradually in patients with progressive pulmonary fibrosis. Acute and subacute disease can progress to a chronic presentation in the absence of appropriate treatment. The most common long-term complication in chronic disease is pulmonary fibrosis that may be accompanied by emphysema, which may lead to respiratory failure or cor pulmonale.
Etiology
An extremely broad range of antigens, generally smaller than 5 µ in size, may trigger HP. The most common sources of these antigens (thermophilic actinomycetes) include farming activities (moldy hay), feces/urine of wild and domestic birds and animals (e.g pigeons and most birds), sources of humidity and exposure to mold, air conditioners, and a long list of rare (often occupational) causes. The disease is caused by a type III or IV hypersensitivity reaction following repeated exposure, possibly in genetically susceptible individuals. This causes diffuse inflammation of the lung parenchyma and airways. Mutations in telomerase-related genes, and polymorphism of the MUC5B gene, have been linked with increased risk of fibrotic HP.
Diagnostic methods
The diagnosis is based on the combination of features, including clinical manifestations, which are determined by performing a physical examination, imaging (HRCT showing diffuse nodules or ground glass opacities in non-fibrotic HP; mosaicism and air trapping in addition to fibrotic features in fibrotic HP), bronchoalveolar lavage (showing an increased level of lymphocytes), positive serology testing (IgG: precipitins), and rarely, lung biopsy. HP may be difficult to diagnose due to non-specific clinical signs. It may be suspected in individuals with manifestations suggestive of HP who have occupational, recreational, or domestic exposure to specific antigens.
Differential diagnosis
Non-fibrotic HP may be confused with allergic asthma, chronic obstructive pulmonary disease, bacterial pneumonia, and recurrent infections. Fibrotic HP may be confused with : idiopathic pulmonary fibrosis, sarcoidosis, and other forms of pulmonary fibrosis.
Management and treatment
Acute forms generally resolve spontaneously on removal of the causative antigen. Short-term treatment of non-fibrotic cases is based on oral corticosteroids. The recommended treatment is prednisone, which may be initiated at 0.5 mg/kg/day and tapered over 2 to 8 weeks. Inhaled corticosteroids and bronchodilators, may also be beneficial. Fibrotic HP may be treated with low-dose prednisone, immunosuppressive therapy especially mycophenolate, and in case of progressive pulmonary fibrosis, antifibrotics. Longer term treatment relies on avoidance of the offending allergen. In occupational settings, risk avoidance may be difficult but can include preventive measures and personal protection equipment.
Prognosis
If the offending antigen is removed, the prognosis of non-fibrotic HP is very good. When detected and treated early, the disease is self-limiting with antigen avoidance. Fibrotic HP is more complicated possibly leading to permanent damage and disability.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Pr Vincent COTTIN


Hypertelorism-hypospadias-polysyndactyly syndrome is a very rare syndrome associating an acro-fronto-facio-nasal dysostosis with genitourinary anomalies.

Summary:
Epidemiology
It has been described in three families.
Clinical description
Craniofacial manifestations include wide anterior fontanel, flat occiput, hypertelorism, ptosis, proptosis, broad nasal bridge and nasal tip, long philtrum and posteriorly rotated or low set ears. Hypospadias and shawl scrotum are present in all males. Acral manifestations include syndactyly of fingers, broad thumbs or halluces or preaxial polydactyly. The affected patients have no intellectual deficit.
Genetic counseling
The condition seems to be hereditary, and transmitted as an autosomal recessive trait.

                            Last update:
                            October 2010


Hypertelorism-microtia-facial clefting syndrome, or HMC syndrome, is a very rare syndrome characterized by the combination of hypertelorism, cleft lip and palate and microtia.

Summary:
Epidemiology
Nine cases have been reported in the literature in seven families.
Clinical description
Some patients have associated cardiac or renal congenital malformations. Short stature and intellectual deficiency are common.
Antenatal diagnosis
Antenatal diagnosis is possible by ultrasonographic monitoring.
Genetic counseling
The reported cases support autosomal recessive inheritance.

                            Last update:
                            March 2010


Hypertelorism-preauricular sinus-punctual pits-deafness syndrome

A rare developmental defect during embryogenesis syndrome characterized by hypertelorism, bilateral preauricular sinus, bilateral punctal pits, lacrimal duct obstruction, hearing loss, abnormal palmar flexion creases and bilateral distal axial triradii. Shawl scrotum has also been reported.


Hypertension due to gain-of-function mutations in the mineralocorticoid receptor

A rare genetic cause of hypertension characterized by severe early-onset therapy-resistant hypertension due to a gain-of-function mutation in the mineralocorticoid receptor. The condition is associated with suppressed plasma renin activity and low serum aldosterone levels and is markedly exacerbated during pregnancy.


Hypertrichosis cubiti is a rare hair anomaly characterized by symmetrical, congenital or early-onset, bilateral hypertrychosis localized on the externsor surfaces of the upper extremities (especially the elbows). Short stature, or other abnormalities, such as developmental delay, facial anomalies and intellectual disability, may or may not be associated.


Hypertrichosis lanuginosa congenita is a rare congenital skin disease characterized by the presence of 3 to 5cm long lanugo-type hair on the entire body, with the exception of palms, soles, and mucous membranes.


Hypertrophic cardiomyopathy with kidney anomalies due to mitochondrial DNA mutation

A mitochondrial oxidative phosphorylation disorder characterized by hypertrophic and dilated cardiomyopathy, failure to thrive, myopathy with generalized hypotonia and increased creatine kinase, developmental delay and/or regression with cerebral atrophy on brain MRI, renal manifestations including chronic renal failure, renal tubular acidosis and lactic acidosis. Additional clinical features include seizures and respiratory failure.


Hypertrophic or verrucous lupus erythematosus is a rare type of chronic cutaneous lupus erythematosus characterized by the appearance of lesions on sun-exposed areas (frequently the extensor surfaces of forearms, face, upper trunk) which vary from squamous violet, painful papules and blackish hyperkeratotic ulcers to depigmented atrophic plaques on the back, hyperkeratotic papules on upper extremities, and disseminated keratoacanthoma-like papulonodular verrucous lesions. Classic discoid lesions and squamous cell carcinoma may be associated. Histopathology reveals follicular plugging, liquefactive basal layer degeneration and a perivascular lymphocytic infiltrate.


A rare inborn error of metabolism characterized by congenital hypertryptophanemia and hyperserotonemia. Patients are typically asymptomatic, although developmental delay, intellectual disability, and behavioral abnormalities, among others, have been reported in association.


Hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome

A rare, genetic, mitochondrial disease characterized by early-onset progressive renal failure, manifesting with hyperuricemia, hyponatremia, hypomagnesemia, hypochloremic metabolic alkalosis, elevated BUN and polyuria, associated with systemic manifestations which include pulmonary hypertension, failure to thrive, global developmental delay, hypotonia and ventricular hypertrophy. Additional features include prematurity, elevated serum lactate, diabetes mellitus and, in some, pancytopenia.


A rare inborn error of zinc metabolism characterized by recurrent infections, hepatosplenomegaly, anemia (unresponsive to iron supplementation) and chronic systemic inflammation in the presence of high plasma concentrations of zinc and calprotectin. Patients typically present dermal ulcers or other cutaneous manifestations (e.g. inflammation) and arthralgia. Severe epistaxis and spontaneous hematomas have also been reported.


A rare headache characterized by recurrent brief, intense headache attacks occurring exclusively during sleep, typically at the same time of the night, causing the patient to wake up. The pain usually lasts more than 15 minutes after waking. It is mostly bilateral and may be associated with nausea, photophobia, or phonophobia, while characteristically no autonomic symptoms are present.


Hypo- and hypermelanotic cutaneous macules-retarded growth-intellectual disability syndrome is a rare, genetic pigmentation anomaly of the skin disorder characterized by congenital hypomelanotic and hypermelanotic cutaneous macules associated with, in some patients, retarded growth and intellectual disability. There have been no further descriptions in the literature since 1978.


Hypobetalipoproteinemia (HBL) constitutes a group of lipoprotein metabolism disorders that are characterized by permanently low levels (below the 5th percentile) of apolipoprotein B and LDL cholesterol.

Summary:
Epidemiology
HBL affects around 1/1,000 individuals.
Clinical description
There are two types of HBL: familial hypobetalipoproteinemia and chylomicron retention disease (CMRD; see these terms). The familial form can be severe with early onset (abetalipoproteinemia/homozygous familial hypobetalipoproteinemia; see this term) or benign (benign familial hypobetalipoproteinemia; see this term). Severe familial HBL and CMRD appear in infancy or childhood. As a result they are often associated with growth delay, diarrhea with steatorrhea, and fat malabsorption. Infants with severe familial hypobetalipoproteinemia have hepatomegaly with steatosis, spastic ataxia, atypical retinitis pigmentosa, acanthocytosis, low levels of liposoluble vitamins (A, E and K), and major cytolysis and even cirrhosis. Benign familial hypobetalipoproteinemia is generally asymptomatic, but in adults is occasionally associated with dietary intolerance to fat, steatorrhea after oral intake of lipids, moderate cytolysis, cholelithiasis, moderately low levels of liposoluble vitamins and acanthocytosis. Moderate hepatic steatosis and paresthesia of the extremities are sometimes observed.
Etiology
HBL disorders are caused by mutations in proteins involved in the synthesis, secretion and catabolism of lipoproteins containing apolipoprotein B (LDL, VLDL and chylomicrons). Abetalipoproteinemia is inherited in a recessive manner and is a result of mutations of two alleles of the MTTP gene (MTP; 4q24). Other severe early familial hypobetalipoproteinemias are inherited in a codominant manner and are a result of mutations of two alleles of the APOB gene (2p24-p23). Benign familial hypobetalipoproteinemia, which is also inherited in a codominant manner, can be caused by heterozygous mutations of the APOB gene or the PCSK9 gene (1p34.1-p32). CMRD, which is inherited in an autosomal recessive manner, is caused by mutations of two alleles of the SAR1B gene (SARA2; 5q31.1).
Diagnostic methods
Diagnosis of familial hypobetalipoproteinemia is based on lipid analysis, after 12 hours of fasting, carried out on the patient and their parents to measure serum levels of LDL (<0.10g/L for the severe form; <0.80g/L for the moderate form), triglycerides (<0.20 g/L for the severe form; <0.50g/L for the moderate form), and apolipoprotein B (<0.10g/L for the severe form; <0.50g/L for the moderate form). Evaluation of steatorrhea and truncated apolipoprotein B after oral lipid intake, measurement of liposoluble vitamins (A, E, K), testing for acanthocytosis (on blood smears), complete neurological examination, hepatic ultrasound and eye examination can also be carried out. Diagnosis of CMRD is based on the absence in serum, after oral lipid intake, of intestinal apolipoprotein B (ApoB-48) and the appearance of `white intestine' seen endoscopically.
Differential diagnosis
Differential diagnoses of HBL include metabolic diseases with hepatic overload, with steatosis and/or hepatomegaly, atypical diseases of the central and peripheral nervous system, and secondary causes of hypocholesterolemia (iatrogenic or systemic).
Antenatal diagnosis
Prenatal diagnosis is feasible when the causal mutations in both parents are known.
Management and treatment
Management of the moderate forms of HBL includes reduction of the proportion of fat in the patient's diet and vitamin E supplementation. Management of the severe forms of HBL and CMRD should take place in specialized centers.
Prognosis
The prognosis of HBL is severe when the disease manifests in early childhood, and is excellent for the moderate form without cytolysis and steatosis. A familial syndrome of longevity has been observed in the benign forms of HBL (many patients live over the age of 85).

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Dr Pascale BENLIAN


A group of rare genetic, vitamin D metabolism disorders characterized by hypocalcemia and rickets, and comprising of hypocalcemic vitamin D dependent rickets (VDDR-I) and hypocalcemic vitamin D resistant rickets (HVDRR). Characteristic clinical features include slow growth, bone pain and bone deformities. HVDRR is associated with resistance to vitamin D treatment.


Hypocalcemic vitamin D-dependent rickets

A rare, genetic disorder of vitamin D metabolism characterized by severe hypocalcemia leading to osteomalacia and rachitic bone deformations, and moderate hypophosphatemia.

Summary:
Epidemiology
The worldwide prevalence in the general population of hypocalcemic vitamin D-dependent rickets (VDDR) is unknown. In Denmark the prevalence among children under 15 years of age is estimated at 1/250,000.
Clinical description
The signs and symptoms vary depending on the severity of the disease. Symptoms can appear within the first year of life with manifestations of chronic hypocalcemia: hypotonia, tetany, seizures, muscle weakness, and poor growth. Progressively, patients present with signs and symptoms of rickets (bowed legs, rachitic rosary...).
Etiology
The disorder is commonly due to inactivating mutations in the CYP27B1 gene (12q14; disorder referred to as VDDR1A) which codes for the enzyme which converts the vitamin D precursor calcidiol to calcitriol. Less commonly, the disorder is due to variants in CYP2R1 (11p15.2; VDDR1B) resulting in decreased expression of vitamin D 25-hydroxylase enzyme which converts calciferol to calcidiol. These defects in the biosynthesis of active vitamin D leads to an impaired intestinal absorption of calcium and phosphate, consequently leading to hypocalcemia and abnormal bone mineralization.
Diagnostic methods
Diagnosis is based on biochemical and radiological findings. Classical radiological signs include rickets and/or osteomalacia and decreased bone mineralization. Biochemical findings include severe hypocalcemia, moderate hypophosphatemia and increase parathyroid hormone and alkaline phosphatase levels. In VDDR1A, additional biochemical anomalies include normal serum levels of calcidiol (25-hydroxyvitamin D) associated with low serum levels of calcitriol (1,25-dihydroxyvitamin D3). In VDDR1B, serum levels of calcidiol (25-hydroxyvitamin D) are undetectable and are associated with normal to high serum levels of calcitriol (1,25-dihydroxyvitamin D3). Diagnosis is confirmed by DNA analysis.
Differential diagnosis
Differential diagnosis includes nutritional vitamin D deficiency, vitamin D resistant rickets and bone dysplasia.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment aims at improving growth and restoring normal serum levels of calcium, phosphorus, alkaline phosphatase, and parathyroid hormone and at healing/preventing skeletal deformities. It consists of daily administration of calcitriol (VDDR1A and VDDR1B). Patients with VDDR1B are also responsive to calcidiol. Nephrocalcinosis, hypercalciuria, and hypercalcemia can be observed as complications of the therapy. Regular monitoring (physical and biochemical examination, hand radiographs, renal ultrasound) is thus required.
Prognosis
With treatment, prognosis is good.

                            Last update:
                            August 2022

                            - Expert reviewer(s):
                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*

                                * European Reference Network


Hypocalcemic vitamin D-resistant rickets

A rare genetic, disorder of vitamin D metabolism characterized by hypocalcemia, severe rickets and in many cases alopecia.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Progressive rickets manifest during the first years of life with poor growth and skeletal deformities. Total body alopecia is present in severe forms of the disease (2/3 of cases). In some cases, skin lesions or epidermal cysts can be observed along with alopecia. The disease presents a broad clinical picture that largely depends on the genotype.
Etiology
The disease is due to mutations in the vitamin D receptor gene (VDR; 12q13-14) that decrease the receptor's action thereby preventing calcitriol's action. This leads to an impaired intestinal absorption of calcium and phosphate.
Diagnostic methods
Diagnosis is based on clinical, biochemical and radiological findings. Biochemical features are severe hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, normal serum levels of calcidiol (25-hydroxyvitamin D), elevated serum levels of calcitriol (1,25-dihydroxyvitamin D3, the active form of vitamin D), and high serum levels of alkaline phosphatase. Radiological findings include typical rickets and/or osteomalacia and decreased bone mineralization. Osteitis fibrosa cystica due to secondary hyperparathyroidism is commonly observed.
Differential diagnosis
Differential diagnosis includes other forms of rickets (hereditary and nutritional) and atrichia with papular lesions (APL) and hypocalcemic vitamin D-dependent rickets.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment aims at improving growth, correcting hypocalcemia and hyperparathyroidism, and at enhancing mineralization of bones. In patients with mild forms it consists of daily administration of high doses of calcitriol and calcium; intravenous administration may be needed in severe phenotypes. Response to treatment largely depends on the severity of the disease. Patients with alopecia generally do not respond to oral treatment and need intravenous calcium infusions. Regular monitoring of biochemical parameters is required.
Prognosis
Correction of rachitic deformities depends on the severity of the disease.

                            Last update:
                            August 2022

                            - Expert reviewer(s):
                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*

                                * European Reference Network


A primary bone dysplasia with micromelia characterized by disproportionate short stature, mild lumbar lordosis and limited extension of the elbow joints.

Summary:
Epidemiology
Hypochondroplasia estimated incidence is 1/50,000. The exact prevalence is unknown.
Clinical description
Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. Radiologic features include shortening of long bones with mild metaphyseal flare; narrowing of the inferior lumbar interpedicular distances; short, broad femoral neck; and squared, shortened ilia. The skeletal features are very similar to those seen in achondroplasia but tend to be milder. Medical complications common to achondroplasia (e.g., spinal stenosis, tibial bowing, obstructive apnea) occur less frequently in hypochondroplasia. Children usually present as toddlers or school-age children with decreased growth velocity leading to short stature and limb disproportion. However, some more severe cases are detected prenatally, at birth or in early infancy. Other features also become more prominent over time.
Etiology
The disorder is caused by mutations in the fibroblast growth factor receptor-3 gene (FGFR3; 4p16.3).
Diagnostic methods
Hypochondroplasia is diagnosed by the recognition of characteristic clinical and radiologic findings that remain controversial. DNA-based testing is possible and about 70% of affected individuals are heterozygous for a pathogenic variant in FGFR3. The most frequent variant is NM_000142.4:c.1620C>A; p.Asn540Lys (p.N540K), which accounts for approximately 60% of affected individuals.
Differential diagnosis
Hypochondroplasia closely resembles achondroplasia (also caused by variants in the FGFR3 gene). Differential diagnosis also includes mild forms of mesomelic dwarfism, mild forms of spondyloepiphyseal-metaphyseal dysplasias, Leri-Weill dyschondrosteosis, Pseudohypoparathyroidism and pseudopseudohypoparathyroidism.
Genetic counseling
The disorder is transmitted in an autosomal dominant manner. Genetic counseling should be proposed to individuals having the disease-causing variant informing them that there is 50% risk of passing the variant to offspring.
Management and treatment
Management of short stature in hypochondroplasia is influenced by parental expectations and concerns; one approach is to address these concerns rather than trying to treat the child. Laminectomy relieves symptoms of spinal stenosis; about 70% of individuals experience relief of symptoms following decompression without laminectomy. Developmental milestones are followed closely during early childhood so that cognitive impairments are addressed with special educational programs. Epilepsy is treated in the standard fashion.
Prognosis
Final adult height varies between 132 and 147 cm and life expectancy is normal.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Dr Karen HEATH


A rare immune complex-mediated small vessel vasculitis characterized by urticaria and hypocomplementemia (low C3, C4 and/or C1q), and usually associated with circulating anti-C1q autoantibodies. Arthritis, pulmonary disease, ocular inflammation are common systemic manifestations.

Summary:
Epidemiology
Prevalence is unknown but less than 500 cases have been reported in the literature. Women are more frequently affected than men (female to male ratio of 8:1).
Clinical description
Patients most commonly present during the fifth decade of life but onset during childhood has been rarely described. Patients present with generalized urticarial eruptions located on the trunk, proximal extremities and face that are often associated with itching or pain and persist for more than 24 hours, with hyperpigmentation after resolution. Angioedema is common and may also be a presenting feature. Cardiorespiratory manifestations include cough, dyspnea, pleural and pericardial effusions, and emphysema, with chronic obstructive pulmonary disease reported in less than 20% of patients. Renal disease is present in 20 to 30% of patients and is generally mild with proteinuria and hematuria caused by glomerulonephritis. However, renal insufficiency and end-stage renal failure have been reported and renal involvement tends to be more severe in patients with childhood onset. Other systemic findings include gastrointestinal symptoms (abdominal pain, nausea, diarrhea, vomiting), musculoskeletal manifestations (arthritis and transient arthralgia affecting the hands, elbows, knees, ankles, and feet), and ocular inflammation (episcleritis, uveitis and conjunctivitis).
Etiology
Hypocomplementemic urticarial vasculitis (HUV) generally occurs sporadically; however, a few familial cases associated with mutations in DNASE1L3 (3p14.3) have been reported. For the majority of cases the etiology is unknown but anti-C1q autoantibodies are believed to be involved in the pathogenesis of the disorder.
Diagnostic methods
Diagnosis requires the presence of two major criteria (recurrent urticaria for > 3 months and hypocomplementemia) and at least two minor criteria (leukocytoclastic vasculitis on biopsy, arthralgia and arthritis, ocular inflammation, abdominal pain, glomerulonephritis and positive anti-C1q autoantibodies).
Differential diagnosis
The relationship of HUV to systemic lupus erythematosus (SLE) is complex with many overlapping features (manifestations of HUV are present in 10% of SLE patients and 50% of patients with HUV will later be diagnosed as having SLE). Other syndromes such as mixed cryoglobulinemia and Schnitzler syndrome should be excluded.
Genetic counseling
The pattern of inheritance for the familial cases associated to DNASE1L3 is autosomal recessive. Genetic counseling is recommended for at risk families.
Management and treatment
Treatment requires tailored therapy with drugs ranging from colchicine, disulone or hydroxychloroquine to more aggressive therapy, such as steroids and immunosuppressives. For example, patients with cutaneous disease and arthralgias but no major organ involvement may be managed with colchicine, hydroxychloroquine, or dapsone; whereas patients with major organ involvement, such as glomerulonephritis, may require high doses of corticosteroids and cytotoxic agents similar to the treatment for active SLE. Response to treatment is usually accompanied by a decrease in circulating anti-C1q titer and normalization of C3 and C4 levels.
Prognosis
The prognosis for HUV patients is variable and influenced primarily by the severity of the rare pulmonary, cardiac and renal disease. When present, pulmonary disease is the major cause of death. Acute laryngeal edema can be life-threatening.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER


Hypodontia-nail dysplasia syndrome is a form of ectodermal dysplasia.

Summary:
Epidemiology
Its incidence has been estimated at around 1-2 in 10,000.
Clinical description
The primary teeth are usually normal but the permanent teeth often fail to erupt. The mandibular incisors, second molars, and maxillary canines are frequently absent and the crowns may be small and conical. Lip eversion may be present. Nails are usually small, thin and brittle with longitudinal ridges, pitting and koilonychias. Congenital absence of the nail plate has also been reported. Toenails are usually more severely affected than fingernails. Sweat glands, heat tolerance and hair are normal, although fine hair has been described in some cases.
Etiology
The syndrome is caused by a mutation in the MSX1 gene (4p16.1).
Diagnostic methods
Diagnosis is usually made during mid-childhood when persistence of the primary dentition becomes apparent, but the syndrome may be difficult to diagnose as the nail defects may be mild.
Differential diagnosis
The differential diagnosis should include other forms of ectodermal dysplasia, in particular hypohidrotic ectodermal dysplasia (see these terms).
Genetic counseling
Transmission is autosomal dominant.
Management and treatment
There is no specific treatment but oral health care and dental management are recommended.
Prognosis
The prognosis is good. The nail defects usually become less apparent with age and the nails often appear normal by adulthood.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Pr Alain VERLOES


A rare multiple congenital anomalies/dysmorphic syndrome characterized by hypoglossia, micrognathia and variable limb abnormalities. Limb defects can involve any limb (usually all four) and the severity may vary from the absence of distal phalanges to total absence of digits or limbs. Synbrachydactyly may also be present. Patients have problems with speech, swallowing and mastication, and they have additional craniofacial anomalies (including telecanthus, lower eyelid defects, broad nose, microstomia, variable clefting or aberrant attachments of tongue, mandibular hypodontia, cleft palate, cranial nerve palsies, and facial asymmetry). Gingival abnormalities are frequently observed. Intelligence and stature are generally normal.


Hypogonadism-mitral valve prolapse-intellectual disability syndrome

This syndrome is characterized by the association of hypogonadism due to primary gonadal failure, mitral valve prolapse, mild intellectual deficit and short stature.

Summary:
Epidemiology
It has been described in two brothers.
Clinical description
Growth hormone (GH) levels and the response to gonadotropin stimulation tests were also abnormal.

                            Last update:
                            May 2009


Hypogonadotropic hypogonadism-frontoparietal alopecia syndrome

This syndrome is characterized by the association of hypogonadotropic hypogonadism and frontoparietal alopecia.

Summary:
Epidemiology
It has been described in six members (four males and two females) of a consanguineous Lebanese family.
Clinical description
In addition to frontoparietal alopecia, the remaining scalp hair was also sparse, and axillary and pubic hair was absent.
Etiology
In contrast to the syndrome of primary hypergonadotropic hypogonadism and partial alopecia (see this term), streak or absent ovaries, hypoplastic uterus, and microcephaly were not reported in the affected female members of this Lebanese family.
Genetic counseling
Despite the family history of consanguinity, autosomal dominant inheritance with reduced penetrance was considered as the most likely mode of transmission.

                            Last update:
                            May 2009


Hypogonadotropic hypogonadism-retinitis pigmentosa syndrome

A rare endocrine syndrome characterized by the association of hypogonadotropic hypogonadism (with primary amenorrhea and lack of secondary sexual development) and retinitis pigmentosa.


Hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome is a rare, non-acquired pituitary hormone deficiency syndrome characterized by severe, congenital microcephaly, facial dysmorphism (highly arched eyebrows, hypertelorism, convex nasal ridge, protruding ears with underdeveloped superior antihelix crus, micrognathia), bilateral sensorineural deafness and hypogonadotropic hypogonadism, in association with early feeding problems, myopia, moderate intellectual disability and moderate short stature.


Hypohidrosis-electrolyte imbalance-lacrimal gland dysfunction-ichthyosis-xerostomia syndrome

A rare genetic disease characterized by abnormalities in renal ion transport, ectodermal gland homeostasis, and epidermal integrity, resulting in generalized hypohidrosis, heat intolerance, salt-losing nephropathy, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia. Development of nephrolithiasis and severe enamel wear have also been described. Laboratory findings include hypermagnesemia, hypokalemia, hypercalcemia, and hypocalciuria.


Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome is a rare, genetic, syndromic intellectual disability disorder characterized by severe intellectual disability with significant speech and language impairment, hypohydrosis (often resulting in hyperthermia) with normal sweat gland appearance, tooth enamel hypoplasia, palmoplantar hyperkeratosis and a high frequency of acquired microcephaly. Mild facial dysmorphism, including lateral flaring of the eyebrows, broad nasal tip, and thick vermilion border, may also be observed.


Hypohidrotic ectodermal dysplasia with immunodeficiency

A rare ectodermal dysplasia syndrome characterized by signs of ectodermal dysplasia (sparse hair, abnormal or missing teeth, decrease or absent sudation), typical facial features (protruding forehead, wrinkles under the eyes, characteristic periorbital hyperpigmentation), and immunodeficiency.

Summary:
Epidemiology
Prevalence is not known. The incidence is approximately 1/250,000 live male births for the X-linked form. Fewer than 10 patients with the autosomal-dominant form have been reported.
Clinical description
The clinical picture is variable. Typical signs of HED may be observed, such as sparse hair (atrichosis/ hypotrichosis), abnormal (e.g. conical) or missing teeth (anodontia/ hypodontia), decreased or absent sudation due to a lack of sweat glands (anhidrosis/ hypohidrosis), and typical facial features (protruding forehead, wrinkles under the eyes, characteristic periorbital hyperpigmentation) which are associated with immunologic defects such as susceptibility to opportunistic infections, hypogammaglobulinemia, impaired antibody response to polysaccharides or impaired NK-cell activity. Many patients fail to thrive. Ectodermal dysplasia-related symptoms of HED-ID, however, tend to be milder than in patients with other forms of HED. The disease can also be associated with osteopetrosis and lymphedema (hypohidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, lymphedema; see this term).
Etiology
HED-ID is caused by hypomorphic mutations in the coding region of the IKBKG (or NEMO) gene (Xq28) or, less often, mutations in the NFKBIA gene (14q13), both involved in NF-κB activation.
Genetic counseling
Transmission is X-linked recessive in case of IKBKG mutations and autosomal-dominant in case of NFKBIA mutations. Somatic mosaicism seems to occur frequently in HED-ID patients.

                            Last update:
                            April 2013

                            - Expert reviewer(s):
                            Pr Holm SCHNEIDER


Hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome

A rare, genetic, ectodermal dysplasia syndrome characterized by the association of hypohidrotic ectodermal dysplasia (manifesting with the triad of hypohidrosis, anodontia/hypodontia and hypotrichosis) with primary hypothyroidism and respiratory tract ciliary dyskinesia. Patients frequently present urticaria pigmentosa-like skin pigmentation, increased mast cells and melanin depositions in the dermis and severe, recurrent chest infections. There have been no further descriptions in the literature since 1986.


A rare genetic ectodermal dysplasia syndrome characterized by sparse hair, abnormal or missing teeth, decrease or absent sudation and typical facial features.

Summary:
Epidemiology
HED has a prevalence of approximately 1/15,000. CST syndrome is the most frequent sub-type (80% of cases) with an incidence in males of 1/50,000 to 1/100,000 births.
Clinical description
HED is characterized by a triad of signs comprising sparse hair (atrichosis/hypotrichosis), abnormal (e.g. conical) or missing teeth (anodontia/hypodontia), and decreased or absent sudation due to a lack of sweat glands (anhidrosis/hypohidrosis) which leads to heat intolerance and may cause recurrent, potentially life-threatening hyperthermic episodes. The skin is thin, dry and eczematous with regional hyperkeratosis. Most of the patients suffer from ''dry eye'' problems (e.g. chronic conjunctivitis, blepharitis), nasopharyngeal dryness and asthma-like symptoms. HED is associated with typical facial features such as a protruding forehead, sparse and fine eyebrows and eyelashes, wrinkles under the eyes, characteristic periorbital hyperpigmentation, a saddle-bridged nose, and hypoplasia of the mandible. Hair pigmentation is often absent or light. Failure to thrive may be observed. The AD and AR forms affect both sexes equally. In the X-linked form, female carriers can be asymptomatic or have a milder phenotype that may include oligodontia, conical incisors, hypotrichosis and moderate hypohidrosis.
Etiology
HED is due to mutations in genes of the ectodysplasin/NF-κB pathway, necessary for the correct development of several ectodermal structures. Mutations in EDA (Xq12-q13.1), encoding the epithelial morphogen ectodysplasin-A of the tumor necrosis factor family, cause the CST syndrome. Mutations in EDAR (2q13), encoding the Ectodysplasin-A receptor, or EDARADD(1q42.3), encoding the EDAR-associated death domain (EDARADD) protein, cause both AR and AD HED.  IKBKG (Xq28) mutations cause HED with immunodeficiency. WNT10A, TRAF6, NFKBIA or EDA2R mutations may be responsible for some HED cases.
Diagnostic methods
The diagnosis is often established after hyperthermic episodes or with delayed teeth eruption. Lack of sweat glands can be evidenced by a skin biopsy or non-invasively by confocal microscopy or graphite prints of feet/hands. Sweat gland function can be assessed by quantifying pilocarpine-induced sweat production. Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnoses include other types of ED like odonto-onycho-dermal dysplasia and certain forms of ichthyosis.
Management and treatment
Uncontrolled exposure to heat must be avoided. Continuous monitoring of body temperature is required for babies placed in an incubator. Older children should adopt physical cooling measures, e.g. frequent consumption of cool liquids, wetting the clothes or wearing special cooling vests/caps. Early dental treatment aims at restoring function and improving the appearance of the teeth. Orthodontic treatment often comprises bone grafting or sinus-lift procedures followed by placement of dental implants supporting dental prostheses. HED with immunodeficiency requires immune-based therapies plus aggressive management of infections or hematopoietic stem cell transplantation.
Prognosis
If the disease is not diagnosed early enough in infancy, hyperthermia may lead to brain damage and eventually death. With early diagnosis and adequate management, most patients have a normal life expectancy.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Pr Holm SCHNEIDER


Hypoinsulinemic hypoglycemia and body hemihypertrophy is a rare, genetic, endocrine disease characterized by neonatal macrosomia, asymmetrical overgrowth (typically manifesting as left-sided hemihypertrophy) and recurrent, severe hypoinsulinemic (or hypoketotic hypo-fatty-acidemic) hypoglycemia in infancy, which results in episodes of reduced consciousness and seizures.


A rare genetic, muscle channelopathy characterized by recurrent episodic attacks of generalized muscle weakness associated with a decrease in blood potassium levels.

Summary:
Epidemiology
Prevalence is estimated at around 1/100,000 in Europe.
Clinical description
Attacks of muscle weakness generally begin during childhood/adolescence (second decade). They vary in frequency, duration (hours to days) and severity (focal paresis to total paralysis). They generally involve the limbs muscles and spare the facial and respiratory musculature. Episodes are triggered by rest after strenuous exercise, meals rich in carbohydrates and prolonged immobility. Other factors may include stress, infection, glucocorticoids, anesthesia and pregnancy. In an undefined number of cases, hypokalemic periodic paralysis (hypoPP) may be associated with a vacuolar myopathy resulting in a permanent and progressive muscle weakness predominantly in proximal lower limb muscles. The myopathy may occur independent of paralytic symptoms.
Etiology
Around 70% of cases are associated with mutations in the muscle calcium channel gene CACNA1S (1q32.1) and 10% of cases are linked to mutations in the muscle sodium channel gene SCN4A (17q23.3).
Diagnostic methods
Diagnosis is based on clinical history, electromyographic and genetic tests. Hypokalemia during attacks can be very low. Serum creatinine kinase (CK) levels can be softly elevated. EMG reveals muscle excitability anomalies after a prolonged exercise test (decrement > 30% of the compound muscle action potential). Muscle biopsy may show non-specific results (muscle fibers atrophy with vacuoles). Molecular diagnosis is feasible through analysis of the causative genes identified so far.
Differential diagnosis
Differential diagnoses should include hyper/normokalemic periodic paralysis, Andersen-Tawil syndrome and secondary hypoPP caused by renal or endocrine diseases such as thyrotoxicosis (thyrotoxic periodic paralysis).
Antenatal diagnosis
Once the pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible but rarely performed because of the non life-threatening prognosis.
Genetic counseling
HypoPP is transmitted as an autosomal dominant disease with a possible incomplete penetrance, especially in females. Genetic counseling should be offered to affected families. Sporadic cases and de novo mutations have been reported. Offspring of a proband are at a 50% risk of inheriting the pathogenic variant.
Management and treatment
Management of patients consists in medical therapy and avoidance of triggering factors. Gentle physical activity, and ingestion of oral potassium salts at the onset of attacks may abort them. Severe attacks require more intensive medical management with intravenous potassium infusion. Daily potassium supplementation or intake of carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide) or potassium-sparing diuretics help in preventing attacks. Dietary advice includes a diet low in carbohydrates and rich in potassium. There is no known curative treatment for hypoPP-related myopathy; physiotherapy may help to maintain strength and motor skills.
Prognosis
With age, the frequency of the episodes decline but some patients may develop a chronic myopathy of variable severity that may cause a permanent muscle weakness.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Savine VICART


Hypomandibular faciocranial dysostosis is a cranial malformation characterized by facial dysmorphism (proptosis, frontal bossing, midface and zygomatic arches hypoplasia, short nose with anteverted nostrils, microstomia with persistent buccopharyngeal membrane, severe hypoglossia with glossoptosis, severe mandibular hypoplasia, and low set ears) associated with laryngeal hypoplasia and craniosynostosis. Other variable features include cleft palate, optic nerve coloboma and choanal stenosis.


Hypomyelination neuropathy-arthrogryposis syndrome is a rare, genetic, limb malformation syndrome characterized by multiple congenital distal joint contractures (incl. talipes equinovarus and both proximal and distal interphalangeal joint contractures of the hands) and very severe motor paralysis at birth (i.e. lack of swallowing, autonomous respiratory function and deep tendon reflexes), leading to death within first 3 months of life. Fetal hypo- or akinesia, late-onset polyhydramnios and dramatically reduced, or absent, motor nerve conduction velocities (<10 m/s) are frequently associated. Nerve ultrastructural morphology shows severe abnormalities of the nodes of Ranvier and myelinated axons.


Hypomyelination of early myelinating structures

A rare genetic neurological disorder characterized by hypomyelination of early myelinating structures such as the brainstem, cerebellar white matter, optic radiation, and periventricular white matter, while structures acquiring myelin later are better myelinated. Patients present in infancy with nystagmus, developmental delay, and progressive ataxic-spastic or ataxic syndrome. Cognitive functions are normal or only mildly impaired.


Hypomyelination with atrophy of basal ganglia and cerebellum

A rare disorder characterized by slowly progressive spasticity, extrapyramidal movement disorders (dystonia, choreoathetosis and rigidity), cerebellar ataxia, moderate to severe cognitive deficit, and anarthria/dysarthria.

Summary:
Epidemiology
So far, around 20 cases have been reported in the literature. The syndrome affects both males and females and onset occurs in infancy or early childhood.
Etiology
The etiology is unknown.
Diagnostic methods
H-ABC is diagnosed on the basis of the distinctive MRI findings of diffuse but partial hypomyelination of the cerebral hemispheres, mild to severe cerebellar atrophy and atrophy of the basal ganglia.
Genetic counseling
All of the reported cases were sporadic and the mode of inheritance remains unclear.

                            Last update:
                            September 2008


Hypomyelination with brain stem and spinal cord involvement and leg spasticity

A rare genetic leukodystrophy characterized by diffuse hypomyelination in the supratentorial brain white matter, brain stem and spinal cord. Patients usually present nystagmus, lower limb spasticity, hypotonia, and motor developmental delay, as well as MRI signal abnormalities involving the corpus callosum, anterior brainstem, pyramidal tracts, superior and inferior cerebellar peduncles, dorsal columns and/or lateral corticospinal tracts.


A rare developmental defect during embryogenesis characterized by congenital or early onset cataracts (usually bilateral), developmental delay, progressive neurologic symptoms (including ataxia, spasticity and sometimes seizures) and mild-to-moderate cognitive impairment. Other major clinical features include truncal hypotonia, dysarthia, cerebellar signs (e.g: truncal titubation and intention tremor) and peripheral neuropathy (e.g: progressive weakness of the muscles in the lower limbs). Hypomyelination associated with periventricular white matter abnormalities is observed. Some patients may have mild lens opacity and cataracts could be absent.


Hypoparathyroidism-sensorineural deafness-renal disease syndrome is a rare, clinically heterogeneous genetic disorder characterized by the triad of hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R).

Summary:
Epidemiology
The exact prevalence is unknown, but the syndrome is considered to be very rare. So far, about 180 individuals from different racial and ethnic groups have been reported in the worldwide medical literature. Patients of both sexes have been described.
Clinical description
HDR syndrome may present at any age with deafness, hypocalcemia, tetany and afebrile convulsions. Since prenatal ultrasonography is now a routine, congenital kidney and urinary tract anomalies could be the first presenting finding. ''H'' occurs in 93% of patients. ''D'' occurs in 96% of patients and is usually bilateral, ranging from moderate to profound impairment. ''R'' occurs in 72% of patients and includes congenital anomalies of the kidney and urinary tract (cystic, dysplastic, hypoplastic or aplastic kidneys, pelvicalyceal deformity, vesicoureteral reflux), chronic kidney disease, nephrotic syndrome, hematuria, proteinuria and others. Several additional features, such as congenital heart disease, facial and ocular abnormalities (retinitis pigmentosa, nystagmus, pseudopapilledema), basal ganglia calcifications, psoriasis, growth failure, and cognitive disability, among others, have also been described.
Etiology
HDR syndrome is primarily caused by mutations in GATA3, located on chromosome 10p (10p14). However, since GATA3 defects have not been detected in all reported patients, the presence of other gene defects being associated is possible. GATA3 belongs to a family of dual zinc-finger transcription factors involved in vertebrate embryonic development of the parathyroid glands, auditory system, and kidneys, as well as the thymus and central nervous system. Variability of expression and incomplete penetrance of GATA3 mutations results in the phenotypic heterogeneity observed.
Diagnostic methods
Diagnosis is based on the clinical findings and may be assisted by measurement of parathormone levels, an audiogram or auditory brain stem response study, renal imaging studies, and, if indicated, a renal biopsy. Although the syndrome is phenotypically defined by the ''HDR'' triad, only 65% of reported patients present it, while the others have various combinations of ''H'', ''D'', and ''R''. Diagnosis is confirmed in patients who have the ''HDR'' triad or, alternatively, have two out of three features plus a positive family history. Patients with isolated deafness or renal disease and those who do not fit the above criteria need positive GATA3 testing to confirm the diagnosis. GATA3 mutations have not been associated with isolated hypoparathyroidism.
Differential diagnosis
Differential diagnoses include familial idiopathic hypoparathyroidism, progressive sensorineural deafness without renal disease, autosomal recessive hypoparathyroidism with renal insufficiency and developmental delay, and deletion 22q11 syndrome. HDR syndrome should be considered in infants prenatally diagnosed with chromosome 10p defect or congenital anomalies of the kidney and urinary tract.
Genetic counseling
Inheritance is autosomal dominant. Family members of affected patients should be studied, investigating for ''H'', ''D'', and ''R''. GATA3 testing should be considered.
Management and treatment
Treatment of patients with HDR syndrome should be comprehensive and should include genetic counseling. Management is essentially symptomatic and depends on the specific clinical findings and severity of the disease. Hypocalcemia is usually the most common problem requiring treatment. Deafness should be treated early with hearing amplification, and, if needed, cochlear implantation. Treatment of kidney disease depends on the particular abnormality and ranges from close observation, such as for cysts, to medical or surgical treatment, including renal transplantation. Chronic kidney disease should be diagnosed and treated early to prevent or delay end-stage renal disease.
Prognosis
Prognosis depends on the nature and severity of the kidney disease. Patients with minor kidney problems have normal life expectancy.

                            Last update:
                            October 2018

                            - Expert reviewer(s):
                            Dr Amin BARAKAT


A rare, genetic metabolic disorder characterized by reduced activity of unfractionated serum alkaline phosphatase (ALP) and various symptoms from life-threatening, severely impaired mineralization at birth to musculo-skeletal pain in adulthood.

Summary:
Epidemiology
Exact prevalence and incidence data for hypophosphatasia (HPP) are not available. In North and West Europe, the birth prevalence of severe forms of the disease (perinatal lethal and infantile forms) has been estimated to be 1/300 000. Because of possible dominant autosomal inheritance, moderate forms of HPP are expected to be more frequent and are estimated to have a prevalence of 1/6300.
Clinical description
Six different clinical forms of HPP have been described, although there is a continuum of severity. Perinatal lethal HPP involves significant hypomineralization and leads to hypercalcemia and respiratory insufficiency. Prenatal benign HPP involves prenatal skeletal manifestations that slowly resolve to become non-lethal. Infantile HPP is characterized by rickets developing between birth and six months of age. Childhood HPP ranges from low bone mineral density with unexplained fractures to rickets. Adult HPP involves early loss of adult dentition and stress fractures of the lower extremities in middle age. In the mildest form, adults may present with only unspecific signs like musculo-skeletal pain or osteoporosis. Lastly, odontoHPP includes premature exfoliation of primary teeth and/or severe dental caries.
Etiology
More than 400 different mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The gene encodes alkaline phosphatase, tissue-nonspecific isozyme (TNSALP) involved in skeletal mineralization.
Diagnostic methods
The diagnosis is based on laboratory testing and molecular genetic testing of the ALPL gene to detect causative mutations. Serum alkaline phosphatase (AP) activity is markedly reduced while 5'pyridoxal phosphate (PLP) in blood and urinary phosphoethanolamine (PEA) are increased but the latter is not pathognomonic. Ultrasound is used in prenatal and perinatal forms. Clinical examinations and radiographs help to establish the diagnosis in infantile, childhood and adult forms.
Differential diagnosis
In the prenatal context, the differential diagnosis includes osteogenesis imperfecta, campomelic dysplasia, hypophosphatemic rickets and achondrogenesis. The main differential diagnosis in other forms is osteogenesis imperfecta.
Antenatal diagnosis
Prenatal diagnosis can be performed through mutation analysis following chorionic villus sampling.
Genetic counseling
Perinatal and severe infantile HPP are typically inherited as autosomal recessive traits. Prenatal benign, moderate infantile, childhood HPP, adult HPP and odontohypophosphatasia can be inherited in an autosomal recessive or autosomal dominant manner, depending on the specific effect the gene mutation has on TNSALP activity. The less severe the disease, the more likely it is dominantly inherited. The range of inheritance patterns partially explains the clinical heterogeneity. In both autosomal recessive and dominant hypophosphatasia, de novo mutations are exceptional. In autosomal dominant hypophosphatasia, affected patients may have an affected parent but penetrance appears to be low. HPP displays highly variable expressivity. Genetic counseling is complicated by these factors but should be offered to affected families.
Management and treatment
Supportive symptomatic treatment in childhood and adult forms includes non-steroidal anti-inflammatory drugs (children), teriparatide (adults) and orthopedic management. Dental monitoring and care are essential. Since its availability, enzyme replacement therapy plays an increasing role, especially in pediatric severe forms.
Prognosis
The perinatal form is almost always fatal within days or weeks. Respiratory complications lead to high mortality rates in the infantile form. Life expectancy is not thought to be affected in childhood and adult forms or in odontohypophosphatasia.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Severine BACROT  - Dr Etienne MORNET


A group of genetic, renal phosphate wasting disorders characterized by hypophosphatemia, rickets, and normal serum levels of calcium. Characteristic clinical features include slow growth/short stature, bone pain and bone deformities.


Hypopigmentation-punctate palmoplantar keratoderma syndrome

A rare, genetic, epidermal disease characterized by punctate keratoderma on palms and soles associated with irregularly shaped hypopigmented macules (typically localized on the extremities). Ectopic calcification (e.g. early-onset calcific tendinopathy, calcinosis cutis) and pachyonychia may be occasionally associated.


A rare, congenital, mitral valve malformation characterized by hypoplastic annulus which usually appears within a complete mitral valve hypoplasia, causing mitral valve stenosis. Association with other cardiac malformation is common, including coarctation of the aorta, aortic valve stenosis, Shone complex and hypoplastic left heart syndrome.


A rare multi-system disease characterized by markedly impaired extracellular fibrinolysis leading to the formation of ligneous (fibrin-rich) pseudomembranes on mucosae.

Summary:
Epidemiology
Whilst epidemiological data is limited, the prevalence of hypoplasminogenemia (HPG) is estimated to be in the range of 1/625,000.
Clinical description
Onset of clinical manifestations usually occurs in early infancy, but can occur at any age. Although not well understood, triggers of lesions may include microtrauma (dust, a foreign body), surgical procedures or local inflammation. The most common clinical manifestation of HPG are lesions of the conjunctivae (ligneous conjunctivitis (LC)) which initially appear as inflammation but progress to development of membranous lesions. Other sites of involvement include the oral cavity with gingival lesions (ligneous periodontitis), nose, sinuses, ears, throat and tonsils, gastrointestinal tract (duodenal ulcers, lesions in the small and large bowel), the respiratory tract (pseudomembranous laryngitis, trachea-bronchitis and consolidation or atelectasis), urinary tract, and the female genital tract (vaginitis, cervicitis, involvement of the fallopian tube, ovary and endometrium). The central nervous system (occlusive hydrocephalus, Dandy Walker malformation) and the skin (juvenile colloid milium) may also be affected, but are less common. HPG has been reported to effect wound healing. HPG is not a risk factor for thrombophilia.
Etiology
HPG is caused by homozygous or compound-heterozygous pathogenic variants in the gene PLG (6q26); encoding plasminogen (plg). In HPG, PLG mutations result in parallel reductions in both the level of immunoreactive plg and its functional activity.
Diagnostic methods
Diagnosis relies on recognition of the clinical manifestations and laboratory tests for plg activity and immunoreactive levels. Diagnosis can be confirmed by genetic testing.
Differential diagnosis
Whilst infection of the affected area is most frequently the assumed diagnosis, the differential diagnosis is extensive and dependent on the area affected and includes polyps, allergies, cholesteatoma, hearing loss, Cowden's Disease, oral fibromas, gingival hypertrophy, reactive airway disease, pneumonia, gastroesophageal reflux disease, ulcers, inflammatory bowel disease, irritable bowel syndrome, kidney stones, endometriosis, polycystic ovarian disease, primary infertility, juvenile colloid milium, Ehlers Danlos (poor wound healing) as well as amyloidosis and lipoid proteinosis.
Antenatal diagnosis
Prenatal genetic diagnosis is possible if a couple has a prior affected child and the pathogenic genetic variants in both PLG genes have been identified. Identification of compound heterozygous or homozygous hypoplasminogenemia is not necessarily predictive of the development of symptoms or severity that may be experienced.
Genetic counseling
HPG is inherited in an autosomal recessive pattern. Siblings of individuals who have hypoplasminogenemia each have a 25% risk of inheriting the condition. Genetic counseling should be offered to families with an affected individual and at-risk couples. Individuals who are heterozygous or have dysplasminogenemia (plg activity is reduced, but immunoreactive levels are normal or slightly reduced) are asymptomatic.
Management and treatment
Management depends on the site(s) of involvement. Treatment strategies have been targeted mainly towards management of LC. The plg concentrate, ryplazim, was recently approved (June 2021, USA) and is administered intravenously as a replacement therapy for plasminogen and has been shown effective in treating both eye and systemic lesions. A currently unlicensed plg ophthalmologic concentrate has been utilized with reported success for eye lesions. In the absence of plg concentrate, treatment is with fresh frozen plasma. Other attempted systemic medications have included anticoagulants, immunosuppressants, hormone therapy, antihistamines, and antibiotics. Surgical interventions have been attempted, but in the absence of plg concentrate, typically result in rapid regrowth of lesions. Occlusive hydrocephalus is treated as standard. Other topical treatments for eye lesions may be used as an adjunctive to plg replacement.
Prognosis
Where the conjunctivae is involved, the visual prognosis is typically moderate; although chronic lesions can lead to loss of vision. The prognosis for severe cases with multiorgan involvement can be quite poor.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Rebecca BIALAS  - Dr Amy SHAPIRO


A rare, congenital, non-syndromic, heart malformation characterized by under development of the left-sided cardiac structures (including left ventricle, ascending aorta, aortic arch, and mitral and/or aortic valve) such that the left heart is unable to provide adequate systemic cardiac output.

Summary:
Epidemiology
Hypoplastic left heart syndrome (HLHS) has been reported to occur in 1/3,500 to 12,500 live births. A male to female predominance ratio of 1.5:1 is observed.
Clinical description
Newborn infants with HLHS are generally born at full term. Initially appearing healthy, they are dependent upon the patent ductus arteriosus (PDA) for systemic blood flow. As the PDA closes, systemic perfusion decreases, resulting in hypoxemia, acidosis, and cardiogenic shock. Usually, no heart murmur (or a non-specific heart murmur) is detected. The second heart sound is loud and single because of aortic atresia. Often the liver is enlarged secondary to congestive heart failure. The spectrum of cardiac malformations can be distinguished by the status of the mitral and aortic valves. At the severe end of the spectrum is the aortic and mitral valve atresia (AA/MA) subtype that is associated with an absent or a slit-like left ventricle and diminutive aortic arch. The two other subtypes, aortic atresia with mitral stenosis (AA/MS), and aortic and mitral stenosis (AS/MS) subtype, have variable ventricular hypoplasia with a discrete left ventricular cavity.
Etiology
As is the case of most congenital cardiac defects, the embryologic cause of the disease is not fully known.
Diagnostic methods
The most useful diagnostic modality is the echocardiogram. Findings on echocardiogram include hypoplasia or atresia of the left ventricle, mitral valve, aortic valve, and ascending aorta.
Differential diagnosis
Differential diagnosis includes other left-sided obstructive lesions where the systemic circulation is dependent on ductal flow (critical aortic stenosis, coarctation of the aorta, interrupted aortic arch).
Antenatal diagnosis
Antenatal diagnosis is possible as the syndrome can be diagnosed by fetal echocardiography between 18 and 22 weeks of gestation.
Management and treatment
Initially, ductal patency is maintained by continuous infusion of intravenous prostaglandin until surgery. Currently, there are two major surgical approaches: univentricular palliation or primary cardiac transplantation, the preference for selecting which option depending on the institutional experience and the availability of donor organs. Univentricular palliation is the most commonly used approach and involves a series of staged cardiac surgical procedures over a period of 2 years that ultimately result in separation of the systemic venous and arterial circulation. Stage I is typically performed in the first week of life, or when the neonate is stable, and techniques may include the Norwood procedure, the Sano modification or the hybrid procedure. Stage II is performed between 3 and 6 months of age and involves the bi-directional Glenn procedure. Stage III, the Fontan procedure, is performed between 2 and 5 years of age. In certain expert centers, fetal transcatheter intervention may be an option. Given the improvement in surgical outcomes, opting for comfort management only remains controversial.
Prognosis
If left untreated, HLHS is universally fatal within a few days- weeks of life. Whilst surgical intervention supports survival through infancy and into early adulthood, the 5-year survival rate is approximately 65%. However, the significant mortality and morbidity associated with both surgical strategies merits discussions with the families regarding the initial decision relative to the treatment and long-term prognosis.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Dr Ravi THIAGARAJAN


Hypoplastic pancreas-intestinal atresia-hypoplastic gallbladder syndrome

A rare, potentially fatal, genetic, visceral malformation syndrome characterized by neonatal diabetes, hypoplastic or annular pancreas, duodenal and jejunal atresia, as well as gallbladder aplasia or hypoplasia. Patients typically present intrauterine growth restriction, failure to thrive, malnutrition, intestinal malrotation, malabsorption, conjugated hyperbilirubinemia, acholia and infections. Cardiac anomalies may also be associated.


A rare, cyanotic congenital heart malformation caused by underdevelopment of the right-sided heart structures (tricuspid valve, RV, pulmonary valve, and pulmonary artery) commonly associated with an atrial septal defect, ostium secundum type. Pulmonary blood flow is diminished and right-to-left shunting occurs at the atrial level, leading to dyspnea, fatigue, atrial arrhythmias, right-sided heart failure, hypoxemia, repeated miscarriages that were mostly due to hypoxemia and cyanosis. Two subtypes of HRHS have been characterized: pulmonary atresia-intact ventricular septum and right ventricular hypoplasia.


Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome

This syndrome is characterized by the association of severe nasal hypoplasia, hypoplasia of the eyes, hyposmia, hypogeusia and hypogonadotropic hypogonadism.

Summary:
Epidemiology
It has been described in two males.
Clinical description
Additional features included bilateral inguinal hernias, undescended testes, and impaired vision with cataracts and colobomata.

                            Last update:
                            May 2009


Hypospadias-intellectual disability, Goldblatt type syndrome

A very rare multiple congenital anomalies syndrome described in three brothers of one South-African family, and characterized by hypospadias and intellectual deficit, in association with microcephaly, craniofacial dysmorphism, joint laxity and beaked nails.


Hypothalamic adipsic hypernatraemia syndrome

A rare endocrine disease characterized by severe chronic hypernatremic dehydration caused by decreased intake of water based on impaired thirst perception, due to a selective defect in hypothalamic osmoregulation of thirst. Structural hypothalamic lesions are absent and arginine vasopressin secretion is normal.


Hypothalamic hamartomas with gelastic seizures is a rare cerebral malformation with epilepsy syndrome characterized by early-onset gelastic (i.e. ictal laughter) or dacrystic (i.e., ictal crying) seizures due to non-neoplastic developmental malformation - hypothalamic hamartomas. In many patients, seizures progress to other seizure types including focal and generalized seizures, with concomitant cognitive decline and behavioral disorders. Some patients also present a precocious puberty.


Hypothyroidism due to deficient transcription factors involved in pituitary development or function

Hypothyroidism due to mutations in transcription factors involved in pituitary development or function is a type of central congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth, characterized by low levels of thyroid hormones caused by disorders in the development or function of the pituitary.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The clinical manifestations can be subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment hypothyroidism results in severe intellectual deficit and short stature. Clinical manifestations may often include signs of hypopituitarism including septo-optic dysplasia or cleft lip and/or palate among others.
Etiology
The hypothyroidism is caused by mutations in genes regulating pituitary gland development including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q) .

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Hypothyroidism due to TSH receptor mutations

A type of primary congenital hypothyroidism, a permanent thyroid hormone deficiency that is present from birth due to thyroid resistance to TSH.

Summary:
Epidemiology
Resistance to TSH occurs in about 5% of cases of permanent congenital hypothyroidism.
Clinical description
Clinical manifestations are those of other forms of congenital hypothyroidism (CH; see this term). Goiter is always absent.
Etiology
Mutations in the TSH receptor gene (TSHR; 14q31) result in resistance to TSH, which causes a reduction in thyroid hormone production. Mutations in TSHR may also cause thyroid hypoplasia (see this term).

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Hypotonia with lactic acidemia and hyperammonemia

This syndrome is characterised by severe hypotonia, lactic academia and congenital hyperammonaemia.

Summary:
Epidemiology
It has been described in three newborns born to consanguineous parents.
Clinical description
Ultrasound examination during the 36th week of pregnancy revealed generalised oedema. Hypertrophic cardiomyopathy and tubulopathy developed within the first week of life and the infants died within the first month. The activities of enzymes in the mitochondrial respiratory chain were reduced in the muscles of the patients.
Etiology
Mutations were identified in the MRPS22 gene, encoding a mitochondrial ribosomal protein.

                            Last update:
                            April 2008


A rare, genetic disorder of amino acid absorption and transport, characterized by generalized hypotonia at birth, neonatal/infantile failure to thrive (followed by hyperphagia and rapid weight gain in late childhood), cystinuria type 1, nephrolithiasis, growth retardation due to growth hormone deficiency, and minor facial dysmorphism. Dysmorphic features mainly include dolichocephaly and ptosis. Nephrolithiasis occurs at variable ages.


Hypotonia-failure to thrive-microcephaly syndrome

Leukotriene C4 synthase deficiency is an extremely rare fatal neurometabolic developmental disorder characterized clinically by muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.


Hypotonia-speech impairment-severe cognitive delay syndrome is a rare, genetic neurodegenerative disorder characterized by severe, persistent hypotonia (presenting at birth or in early infancy), severe global developmental delay (with poor or absent speech, difficulty or inability to roll, sit or walk), profound intellectual disability, and failure to thrive. Additional manifestations include microcephaly, progressive peripheral spasticity, bilateral strabismus and nystagmus, constipation, and variable dysmorphic facial features (including plagiocephaly, broad forehead, small nose, low-set ears, micrognathia and open mouth with tented upper lip).


Hypotrichosis simplex of the scalp (HSS) is characterized by diffuse progressive hair loss that is confined to the scalp.

Summary:
Epidemiology
Prevalence is unknown but HSS has been described in multiple members (males and females) of several large families.
Clinical description
Progressive hair loss generally begins during the first decade of life and most patients are completely bald by the third decade of life. In contrast to the generalized form of hypotrichosis simplex (see this term), body, axillary and facial hair, as well as the eyebrows and eye lashes are unaffected in HSS. There are no anomalies of the skin, nails and teeth.
Etiology
The causative gene CDSN (encoding the keratinocyte adhesion molecule, corneodesmosin) has been mapped to chromosome 6p21.3.
Genetic counseling
HSS is transmitted in an autosomal dominant manner.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Pr Regina BETZ


Hypotrichosis simplex (HS) or hereditary hypotrichosis simplex (HHS) is characterized by reduced pilosity over the scalp and body (with sparse, thin, and short hair) in the absence of other anomalies.

Summary:
Epidemiology
Prevalence is unknown but numerous large pedigrees with several affected members have been described. Both men and women are equally affected.
Clinical description
Hair loss is diffuse and progressive and usually begins during early childhood. Body hair may also be sparse with variable involvement of the eyebrows, eyelashes, and pubic and axillary hair. There are no anomalies of the skin, nails or teeth. A scalp-limited form, hypotrichosis simplex of the scalp (see this term) has also been reported with mutations in the corneodesmosin (CDSN) gene.
Etiology
Both autosomal dominant and recessive modes of transmission have been reported for HHS.Autosomal dominant HHS affecting both scalp and body hair has been reported in one Italian and two Pakistani families as due to mutations in the APCDD1 gene mapped to 18p11.22. Three clinically similar forms of localized autosomal recessive hypotrichosis (LAH1, LAH2 and LAH3) have been identified within the last years. The locus for LAH1 (involving mainly the hair of the scalp, chest, arms and legs) has been mapped to 18q12.1 and mutations in the desmoglein-4 (DSG4) gene have been identified. The locus for LAH2 (characterized by sparse or absent scalp, axillary and body hair, and sparse eyebrows and eyelashes) has been mapped to 3q27.3 and mutations in the lipase-H (LIPH) gene have been identified. The locus for LAH3 (characterized by progressive loss of scalp hair, sparse body hair, and normal eyebrows, eyelashes, and pubic and axillary hair) has been mapped to 13q14.11-q21.32 and mutations have been identified in a G protein-coupled receptor gene (P2RY5). These receptors belong to the group of lipophosphatidic acid (LPA) receptors and are therefore designated as LPAR6.
Management and treatment
There is no treatment for hypotrichosis simplex available to date.

                            Last update:
                            June 2010

                            - Expert reviewer(s):
                            Pr Regina BETZ


Hypotrichosis with juvenile macular degeneration (HJMD) is a very rare syndrome characterized by sparse and short hair from birth followed by progressive macular degeneration leading to blindness.

Summary:
Epidemiology
Prevalence is unknown but approximately 50 patients have been described since the first characterization of the syndrome in 1935.
Clinical description
HJMD patients present with short and sparse scalp hair since birth or first months of life, with no subsequent growth during life. A decade later, during the first to third decades of life, visual acuity decreases because of progressive macular degeneration, leading in many cases to blindness between the second and fourth decades of life. HJMD is sometimes associated with limb anomalies, in which case it is termed Ectodermal dysplasia, Ectrodactyly, and Macular dystrophy (EEM; see this term). Many patients display fair hair complexion as compared with their healthy siblings. The hair phenotype does not improve significantly with age, even though diffuse alopecia in infancy can evolve towards short and sparse hair in puberty.
Etiology
HJMD is caused by mutations in the CDH3 gene (16q22.1), encoding P-cadherin. P-cadherin is part of adherens junctions in various epithelia including the hair follicular epithelium. Moreover, P-cadherin is expressed in the retinal pigment epithelium.
Diagnostic methods
Diagnosis is based on the combined occurrence of hypotrichosis with characteristic degenerative changes and pigmentary abnormalities of the macula on fundoscopy. Where available, electrophysiologic studies can confirm abnormal function of the posterior pole. Additional tests of lesser diagnostic value include (1) histopathologic examination of scalp biopsies, revealing mostly vellus and catagen hair follicles with significantly reduced number of terminal hair follicles; (2) light microscopy and scanning electron microscopy of hair which can demonstrate various structural abnormalities including pseudomonilethrix, pili torti, longitudinal ridging, scaling and folding of the hair shaft.
Differential diagnosis
Differential diagnosis includes EEM syndrome, also caused by CDH3 mutations.
Antenatal diagnosis
DNA-based prenatal diagnosis and genetic counseling are available provided the underlying mutation is known.
Genetic counseling
As HJMD is an autosomal recessive disease, risk of recurrence is 25%.
Management and treatment
No curative or palliative options exist for HJMD. However, educational measures can be implemented and psychological support should be provided once HJMD is diagnosed.
Prognosis
The most severe complication of HJMD is progressive macular degeneration leading to blindness between the second and fourth decades of life. Life expectancy is normal but quality of life can be reduced because of blindness and psychological impact due to the hair phenotype.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Dr Liat SAMUELOV  - Pr Eli SPRECHER


A syndromic genetic deafness characterized by erythrokeratoderma, hypotrichosis, nail dystrophy and sensorineural hearing loss. Erythema, recurrent skin infections and mucositis have also been associated.


Hypotrichosis-intellectual disability, Lopes type

A rare ectodermal dysplasia syndrome characterized by hypotrichosis of scalp and eyebrows, finger syndactyly, intellectual disability and early eruption of teeth. Facial dysmorphism (i.e. round face with prominent forehead, cheeks and ears, and upward-slanting palpebral fissures), hypoplasia of median and distal phalanges, and kyphosis are additionally observed features. There have been no further descriptions in the literature since 1996.


An extremely rare syndromic lymphedema disorder characterized by early-onset hypotrichosis, childhood-onset lymphedema, and variable telangiectasia, particularly of the palms.


Hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome is an extremely rare ectodermal dysplasia syndrome characterized by hypotrichosis universalis with mild to severe scarring alopecia, acro-osteolysis, onychogryphosis, thin and tapered fingertips, periodontitis and caries leading to premature teeth loss, linear or reticular palmoplantar keratoderma and erythematous, scaling, psoriasis-like skin lesions on arms and legs. Lingua plicata and ventricular tachycardia have also been observed.


Hypoxanthine guanine phosphoribosyltransferase partial deficiency

Kelley-Seegmiller syndrome (KSS) is the mildest form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (see this term), a hereditary disorder of purine metabolism, and is associated with uric acid overproduction (UAO) leading to urolithiasis, and early-onset gout.

Summary:
Epidemiology
The exact prevalence is unknown but is probably underestimated due to misdiagnosis. KSS may represent about 15% of HPRT deficient patients.
Clinical description
Age of onset is usually in infancy but can also be in adulthood (up to 30 years). Males are generally affected and heterozygous females are carriers (usually asymptomatic). Patients are normal at birth. The first manifestation is the presence of orange crystals in diapers. Urolithiasis, uric acid nephropathy, urinary infections and renal obstruction are often the presenting symptoms. Gout may appear after puberty with acute arthritis or tophi. In contrast to Lesch-Nyhan syndrome (LNS; see this term), dystonia may be mild or even absent. Patients have normal intelligence associated with various degrees of attention deficit. Compulsive self-injurious behavior is absent.
Etiology
The disease is caused by partial HPRT deficiency due to mutations in the HPRT1 gene (Xq26). Inheritance is X-linked recessive. UAO may be due to deficient recycling of purine bases with increased synthesis of purine nucleotides leading to hyperuricemia that increases the risk of UA crystal precipitation in tissues to form tophi, in joints leading to inflammatory processes and gouty arthritis, and renal UA excretion causing urolithiasis.
Diagnostic methods
Diagnosis may be suspected when nephrolithiasis and/or obstructive nephropathy occur and is based on biochemical, enzymatic and molecular tests. Hyperuricemia and UAO are detectable in serum and urine. Plasmatic levels and urinary excretion of urate, hypoxanthine, and, to a lesser extent, xanthine are elevated. HPRT activity in hemolysate ranges from 0.5% to 10%.
Differential diagnosis
Differential diagnosis includes glucose 6-phosphate dehydrogenase deficiency, Lesch-Nyhan syndrome and phosphoribosylpyrophosphate (PRPP) synthetase superactivity (see these terms).
Antenatal diagnosis
Antenatal diagnosis is usually not required.
Management and treatment
UAO, nephrolithiasis, gouty arthritis and tophi can be managed with allopurinol, urine alkalinization (sodium bicarbonate or citrate) and generous hydration. Doses must be carefully adjusted to avoid xanthine lithiasis.
Prognosis
With appropriated treatment renal function remains stable and patients have a normal life expectancy.

                            Last update:
                            April 2010

                            - Expert reviewer(s):
                            Dr Juan GARCÍA PUIG  - Dr Rosa TORRES JIMÉNEZ


Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a hereditary disorder of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzyme deficiency.

Summary:
Epidemiology
Prevalence of HPRT deficiency is unknown but estimated prevalence for Lesch-Nyhan syndrome (LNS; see this term) is estimated between 1/380,000 and 1/235,000 live births. Males are generally affected and heterozygous females are carriers (usually asymptomatic).
Clinical description
Onset occurs during infancy. Two forms of the disease have been described: LNS, the most severe form, with a complete enzyme deficiency, and Lesch-Nyhan variants with partial HPRT deficiency. LNS is characterized by uric acid overproduction-related symptoms associated with urolithiasis and gout, severe neurological manifestations, hematological disturbances, and compulsive self-injurious behaviour. LNS patients have a limited life expectancy. In the less severely affected LNS variants, also termed Kelley-Seegmiller syndrome (KSS; see this term), uric acid overproduction-related symptoms are prominent, neurological manifestations are usually unapparent, compulsive self-injurious behaviour is absent and patients have a normal life expectancy.
Etiology
Inheritance is X-linked recessive and HPRT deficiency results from mutations in the HPRT1 gene (Xq26).

                            Last update:
                            April 2010

                            - Expert reviewer(s):
                            Dr Juan GARCÍA PUIG  - Dr Rosa TORRES JIMÉNEZ


Iatrogenic botulism is the most recent man-made form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), and it may occur as an adverse event after therapeutic or cosmetic use.

Summary:
Epidemiology
Prevalence is unknown. As of 2008, 180 cases occurring between 1997 and 2006 have been reported to the FDA, including 87 hospitalized cases and 16 deaths.
Clinical description
Clinical manifestations are similar to other forms of botulism, with symmetrical cranial nerve palsies followed by descending, symmetric flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death.
Etiology
After injection, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism. Therapeutic BoNT injections are a first-line treatment for hemifacial spasm and focal dystonia, such as cervical dystonia and blepharospasm (see these terms). They can also be proposed to treat strabismus and other oculomotor disorders, focal spasticity (spastic foot, upper and lower limb spasticity), overactive bladder and autonomic disorders such as hyperhidrosis, Frey's syndrome and sialorrhea. BoNT injections may have a potential antinociceptive effect. Injected doses, that may be relatively high mostly in the treatment of lower limb spasticity, have caused events reported as adverse reactions including limited botulism-related symptoms (ptosis, diplopia, dysphagia), rare systemic events (flu-like syndrome, generalized weakness and respiratory distress) and occasional deaths following the use of BoNT types A and B. Doses recommended for cosmetic treatment are too low to cause systemic disease, but injection of unlicensed, highly concentrated botulinum toxin may cause severe botulism. All cases of botulism should be reported to the appropriate government agency.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Michel POPOFF


A rare acquired human prion disease characterized by progressive, invariably fatal neurodegeneration resulting from accidental transmission of CJD prions in the course of medical procedures or treatments (treatment with human pituitary growth hormone or gonadotrophin, human dura mater or corneal graft, exposure to contaminated neurosurgical instruments). Patients present rapidly progressive cognitive impairment, as well as myoclonus, visual or cerebellar problems, pyramidal or extrapyramidal features, and/or akinetic mutism. EEG examination may show characteristic generalized periodic sharp wave complexes. Neuropathologic analysis reveals spongiform change, neuronal loss and gliosis, and deposition of abnormal prion protein.


A rare autosomal recessive syndrome with combined immunodeficiency characterized by the clinical triad of immunodeficiency, centromeric instability and facial anomalies (abbreviated ICF syndrome). The immunodeficiency is with panhypogammaglobulinemia, and a lack of memory (CD19+CD27+) B cells in the peripheral blood, although B and T-cell counts are normal. Anomalies and rearrangements associated with DNA hypomethylation in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9, in mitogen-stimulated lymphocytes, is a hallmark of the syndrome. The typical facial anomalies include hypertelorism, low-set ears, epicanthus and macroglossia.

Summary:
Epidemiology
ICF has been described in about 100 patients worldwide.
Clinical description
Recurrent infections are the presenting symptom, usually in early childhood. Autoimmune manifestations have been described. Other variable symptoms of this probably under-diagnosed syndrome include delayed developmental milestones with growth delay, failure to thrive, and global developmental delay, with various degrees of cognitive impairment.
Etiology
The syndrome is caused by homozygote or heterozygote mutations in the DNA methyltransferase 3B (DNMT3B; ICF1), the zinc finger and BTB domain containing 24 (ZBTB24; ICF2), the cell division cycle-associated 7 (CDCA7; ICF3), the helicase lymphoid specific (HELLS; ICF4) genes. More recently, variants in the ubiquitin like with PHD and ring finger domains 1 gene (UHRF1) have been associated with one ICF patient. Loss of DNA methylation at satellite repeats embedded in the juxta-centromeric heterochromatin in the 1qh, 9qh, and 16qh, regions is a hallmark of ICF patients and is associated with whole-arm deletions, chromatid and chromosome breaks, stretching (decondensation), and multiradial chromosome junctions in mitogen-stimulated lymphocytes. DNA hypomethylation at centromeric satellite repeats (alpha-satellite), at subtelomeres and a set of unique genes are linked to the genotype of the patients.
Diagnostic methods
Diagnosis is suspected on clinical presentation, mostly on recurrent infections and immunologic abnormalities (very low memory B cells). Molecular investigations based on cytogenetic analysis and gene panel sequencing enable to confirm the diagnosis.
Differential diagnosis
The differential diagnosis includes other syndromic combined immunodeficiencies.
Antenatal diagnosis
Prenatal diagnosis is available for this disorder.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is proposed to family with ICF syndrome. At-risk couples (both individuals are carriers of a disease-causing mutation) have a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment includes regular infusions of immunoglobulins, mostly intravenously, and antibacterial prophylaxis. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for ICF patients.
Prognosis
HSCT can cure the immunodeficiency of patients with ICF syndrome. Very few cases have been reported (less than 10 cases) and only for patients with mutations in the DNMT3B gene (ICF1). Long-term follow-up studies are limited.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                            Pr Capucine PICARD  - Dr Guillaume VELASCO


Ichthyosis follicularis - alopecia - photophobia (IFAP) is a rare genetic disorder characterized by the triad of ichthyosis follicularis, alopecia, and photophobia from birth.

Summary:
Epidemiology
Prevalence is unknown. Approximately 40 cases have been reported to date. IFAP primarily affects male subjects. Female carriers may develop some clinical features.
Clinical description
All patients present with congenital follicular ichthyosis, alopecia involving the scalp, eyebrows and eyelashes, and photophobia (in the first year of life, infancy or early childhood). Ichthyosis follicularis is characterized by widespread non-inflammatory thorn-like follicular projections. Hyperkeratotic papules are most pronounced over the extensor extremities and scalp and are distributed symmetrically. Non-cicatricial complete body alopecia is also a classical feature. Variable degrees of a collodion membrane may be present in newborns. Psoriasiform plaques, angular cheilitis, periungueal inflammation, dystrophic nails, hypohidrosis and atopic eczema can be present. The palms and soles are generally unaffected. Superficial corneal ulceration and vascularization may lead to progressive corneal scarring. Male patients have relentless progression of corneal vascularization and loss of vision. Atopic keratoconjunctival inflammation, chronic tearing, cataract, horizontal nystagmus, astigmatism and myopia have been reported. In a few cases, mild to severe intellectual disability, short stature, microcephaly, seizures, dysmorphic features (frontal bossing, choanal atresia, large ears), cleft hands, intestinal anomalies (omphalocele, Hirschsprung disease or congenital aganglionic megacolon (see these terms), small intestine stenosis, inguinal hernia), as well as renal, cardiac and vertebral anomalies can be present. Recurrent infections are common. External genitalia are generally normal with a few cases of cryptorchidism and one with hypospadias. Affected or carrier females may have milder symptoms (cutaneous hyperkeratotic lesions that follow the lines of Blaschko, asymmetric distribution of body hair, patchy alopecia).
Etiology
The disorder is caused by mutations in the MBTPS2 gene (Xp22.12-p22.11) leading to impaired cholesterol homeostasis and response to endoplasmic reticulum stress.
Diagnostic methods
Diagnosis is based on the clinical features and on testing of the MBTPS2 gene.
Differential diagnosis
Differential diagnosis includes dermotrichic syndrome, hereditary mucoepithelial dysplasia, keratitis-ichthyosis-deafness (KID syndrome) and keratosis follicularis spinulosa decalvans (see these terms).
Antenatal diagnosis
IFAP cannot be detected prenatally by ultrasound.
Genetic counseling
If the mutation has been identified in a carrier mother, prenatal diagnosis can be proposed. Transmission is X-linked recessive. The mutation might also arise de novo. A few cases of autosomal dominant inheritance have been reported.
Management and treatment
Follicular hyperkeratosis can be treated using topical keratolytics, emollients and urea preparations. A moderate response to acitretin therapy has been found in some patients. Intensive lubrication of the ocular surface is essential. Corneal vascularization does not respond to topical corticosteroids.
Prognosis
Prognosis is variable. Some patients die in the neonatal period while others have normal life expectancy. However, in most patients, progressive loss of vision leads to loss of autonomy. Cardiopulmonary complications are the main cause of death.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr André MEGARBANE  - Dr Hala MEGARBANE


Ichthyosis hystrix of Curth-Macklin (IHCM) is a rare type of keratinopathic ichthyosis (see this term) that is characterized by the presence of severe hyperkeratotic lesions and palmoplantar keratoderma (PPK, see this term).

Summary:
Epidemiology
Prevalence is unknown. Six families and sporadic cases have been reported to date.
Clinical description
The skin is usually normal at birth. The disease starts in early childhood with severe hyperkeratosis of yellow-brown or grey color, and of spiky, cobblestone-like (hystrix) or verrucous appearance. Hyperkeratosis is often diffuse and more pronounced on extensor areas of the limbs, extremities and the trunk. Lesions may also be nevoid following the lines of Blaschko. Patients are also affected with striate or diffuse PPK. As the disease progresses, PPK worsens and results in deep bleeding, painful fissures and cracks. In severe cases, PPK can also lead to contractures, gangrene and loss of digits. The skin is malodorous and frequently infected. Nail dystrophy may be present. Contrary to other keratinopathic ichthyoses, no skin fragility/blister formation or erythroderma is present.
Etiology
IHCM results from heterozygous frameshift mutation in a section of the KRT1 gene encoding keratin 1 (K1). These mutations lead to an abnormal supramolecular organization of keratin intermediate filaments and may be related to defects in cytoplasmic trafficking and integrity of cellular structures such as organelles and nucleus.
Diagnostic methods
Diagnosis is based on clinical examination and on histological examination of skin lesion biopsies revealing papillomatous hyperplasia with hyperorthokeratosis and hypergranulosis. Electron microscopy shows keratin intermediate filaments forming continuous perinuclear shells, presence of perinuclear vacuoles and binucleate keratinocytes.
Differential diagnosis
Differential diagnosis includes other forms of keratinopathic ichthyosis such as epidermolytic ichthyosis, as well as epidermolytic palmoplantar keratoderma, erythrokeratodermia variabilis, and KID syndrome (see these terms).
Antenatal diagnosis
Molecular prenatal diagnosis is available for affected families.
Genetic counseling
Transmission is autosomal dominant but some sporadic cases have been reported. The risk for an affected parent to have an affected child is of 50%.
Management and treatment
Management is symptomatic and life-long. Oral and systemic keratolytics can improve localized hyperkeratotic lesions by exfoliating and increasing the moisture of the skin.
Prognosis
Life expectancy is normal. However, the unaesthetic and malodorous aspects of the skin, the pain and bleeding related to PPK, and infections lead to functional disabilities and a greatly reduced quality of life.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER


Ichthyosis-alopecia-eclabion-ectropion-intellectual disability syndrome is an ectodermal dysplasia syndrome characterized by severe generalized lamellar icthyosis at birth with alopecia, eclabium, ectropion and intellectual disability. Although similar to Sjögren-Larsson syndrome, this syndrome lacks the presence of neurologic or macular changes. There have been no further descriptions in the literature since 1987.