Hereditary sensory and autonomic neuropathy type 1

A rare slowly progressive neurological disorder characterized by prominent predominantly distal sensory loss, autonomic disturbances in some patients, autosomal dominant inheritance, and juvenile or adulthood disease onset.

Summary:
Epidemiology
The exact prevalence is unknown, but is estimated as very low.
Clinical description
Disease onset varies between the 2nd and 5th decade of life. Early onset is occasionally reported. The main clinical feature of hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a reduction of sensation sense, mainly distributed around the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Spastic paraparesis, or cough and gastroesophageal reflux have been observed in rare cases.
Etiology
HSAN1 is a genetically heterogenous condition with several loci and mutations in four genes (SPTLC1, SPTLC2, ATL1, ATL3) identified so far. DNMT1 gene variants also lead to a specific form of the disease, HSAN1E, clinically distinct due to the presentation of dementia and hearing loss.
Diagnostic methods
Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when complications such as bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the above mentioned genes. DNMT1-associated disease is clinically distinct from the other HSAN1 subtypes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counseling and prognosis.
Differential diagnosis
Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumors like amelanotic melanoma.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. However, availability depends on country-specific regulations.
Genetic counseling
Transmission is autosomal dominant; whilst several cases occur sporadically, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Management of HSAN1 largely follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. Preclinical and clinical trials are ongoing for SPTLC-associated disorders (L-Serine therapy).
Prognosis
The disorder is slowly progressive and may not influence life expectancy in many cases but is often severely disabling after a long duration of the disease. Early-onset severe cases are reported.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Pr Ingo KURTH


Hereditary sensory and autonomic neuropathy type 1B

Hereditary sensory and autonomic neuropathy, type 1B (HSAN1B) is characterized by the association of type 1 HSAN with paroxysmal cough and gastroesophageal reflux (GOR).

Summary:
Epidemiology
So far, it has been described in two families.
Clinical description
Onset occurs in adulthood with distal sensory loss due to an axonal neuropathy, GOR, and cough triggered by noxious odors or by pressure in the external auditory canal. The cough may be severe leading to syncope and retinal detachment. Additional features include throat clearing, a hoarse voice, and sensorineural hearing loss.
Etiology
Linkage to chromosome 3p22-p24 was found in both reported families.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            January 2009


Hereditary sensory and autonomic neuropathy type 2

A rare hereditary sensory and autonomic neuropathy characterized by profound and universal sensory loss involving large and small fiber nerves.

Summary:
Epidemiology
To date, less than 100 cases have been reported. There is no sex preference or particular ethnic preponderance.
Clinical description
Disease onset is typically in infancy and is non-progressive. Initial symptoms (from birth to 3 years) include lack of crying with trauma, self-mutilation (tongue, lips), swallowing and feeding problems. Gastroesophageal reflux is common. Sensory dysfunction is manifested by reduced or absent pain and temperature perception, and depressed or absent deep tendon reflexes. Corneal reflexes are reduced or absent. Muscle strength is preserved and there is no atrophy. Sensation to fine touch, position, vibration, taste, and gag reflexes may be diminished. Unrecognized injuries (e.g., burns, skin and corneal ulcers) and fractures of hands, feet, and limbs, sometimes resulting in osteomyelitis, as well as Charcot joints are frequent. Some patients have hearing loss. Autonomic involvement is limited to reduced lacrimation. Patients do not typically have orthostatic hypotension or sweating abnormalities.
Etiology
Causal mutations in several genes have been identified and include SCN9A (2q24.3), WNK1 (12p13.33), RETREG1  (5p15.1), and KIF1A  (2q37.3), all of which appear to be involved in the development of sensory nerves.
Diagnostic methods
Diagnosis is based upon clinical features (congenital onset of severe reduction in sensory modalities and deep tendon reflexes resulting in injuries and self-mutilation). Neurophysiological evaluation (showing slow sensory conduction velocities and amplitudes), electromyogram and electroencephalographic studies support the diagnosis. Targeted genetic testing identifying described mutations in causatives genes is confirmatory. For cases in which no genetic mutation can be identified with targeted genetic testing, whole exome sequencing may identify novel variants/genes.
Differential diagnosis
Differential diagnosis includes the other hereditary sensory and autonomic neuropathies, the most similar of which include hereditary sensory and autonomic neuropathy type 4 (characterized by complete lack of pain and complete lack of sweating), familial dysautonomia (accompanied by baroreflex abnormalities with paroxysmal episodes of nausea, retching, vomiting and hypertension) and hereditary sensory and autonomic neuropathy type 1 (typically adult-onset).
Genetic counseling
The pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers. Penetrance is always complete, but the severity of the disease is variable.
Management and treatment
Management is symptomatic and preventative. If feeding problems compromise nutrition and if gastroesophageal reflux is also present, fundoplication with gastrostomy might be considered. Parents' and patients' education is required to learn how to avoid injury and be alert for signs of unrecognized trauma. Reduced lacrimation requires artificial tears and corneal protective lenses to prevent corneal ulcers.
Prognosis
No natural history studies have been performed. Most patients reach adulthood.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Horacio KAUFMANN  - Pr Jose-Alberto PALMA


Hereditary sensory and autonomic neuropathy type 4

A rare hereditary sensory and autonomic neuropathy characterized by anhidrosis, insensitivity to pain, self-mutilating behavior and episodes of fever.

Summary:
Epidemiology
Whilst several hundred cases have been reported worldwide, the exact prevalence is unknown. Most of the cases described were from the Israeli Bedouin population and Japan where the prevalence is estimated at 1/600,000-950,000.
Clinical description
The disease typically presents in early infancy, but may occasionally present during the neonatal period. Consanguinity has been reported in 50% of patients. Episodic fevers without obvious infections, extreme hyperpyrexia and febrile convulsions due to inability to dissipate heat as a result of anhidrosis as well as self-mutilation are usually the earliest signs of the disease. The cardinal feature is absence of sweating on the trunk and extremities, with occasional patients producing some moisture on the forehead, tip of the nose and gluteal sulcus. The skin becomes thick and callused with lichenification of palms, areas of hypotrichosis on the scalp and dystrophic nails. Deep tendon reflexes are usually present. Pain insensitivity is profound resulting in self-mutilation, auto-amputation, and corneal scarring but some patients retain temperature perception. Vibration sense and proprioception are normal or moderately decreased Bone fractures are slow to heal and large weight bearing joints are particularly susceptible to repeated trauma and frequently go on to the development of Charcot joints and osteomyelitis. Hypotonia and delayed developmental milestones are frequent in the early years, but sometimes normalize with age. Speech is usually clear, but patients have severe learning difficulties, irritability, hyperactivity, and cognitive impairment. Normal intelligence, however, has been reported in a few patients. Mild postural hypotension with compensatory tachycardia may be present, but not episodic hypertension. Around 20% of patients have scoliosis.
Etiology
The disease is due to mutations in the gene NTRK1 (1q21-22).
Diagnostic methods
Diagnosis requires two clinical criteria: anhidrosis and decreased pain perception, and is confirmed by genetic testing identifying variants in NTRK1. Skin biopsy reveals deficient C and A-delta fibers in the epidermis and hypoplastic dermal sweat glands without innervation. Plasma concentration of norepinephrine is extremely low or undetectable but epinephrine, vasopressin and plasma renin activity are normal.
Differential diagnosis
Differential diagnosis includes other hereditary sensory and autonomic neuropathies from which it is distinguished by absent or markedly decreased sweating.
Genetic counseling
The pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers.
Management and treatment
Management is supportive and oriented to control hyperthermia, prevention of self-mutilation and treatment of orthopedic problems that potentially can cause severe and invalidating deformities. It is necessary to help families cope with behavioral and educational issues.
Prognosis
The prognosis for independent functions depends on the degree of disease expression and the ability to control the secondary clinical problems.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Horacio KAUFMANN  - Pr Jose-Alberto PALMA


Hereditary sensory and autonomic neuropathy type 5

A disorder that is characterized by loss of pain perception and impaired temperature sensitivity, in the absence of any other major neurological anomalies.

Summary:
Epidemiology
Prevalence is unknown. Only a small number of cases have been described in the literature, although one large multigenerational consanguineous family from northern Sweden has been reported.
Clinical description
Other findings include ulcers, self-mutilation and damaged joints. Intelligence is normal.
Etiology
Mutations in the NGF gene (1p13.1) were detected in affected members of the large Swedish family. However, mutations in the NTRK1 gene (1q21-q22) have been identified in one patient diagnosed with HSAN5 with the additional finding of mild anhidrosis. Mutations in the NTRK1 gene have also been implicated in the more severe HSAN subform, HSAN4 (congenital insensitivity to pain with anhidrosis; see this term).
Genetic counseling
The syndrome is transmitted in an autosomal recessive manner

                            Last update:
                            January 2009


Hereditary sensory and autonomic neuropathy type 6

A rare hereditary sensory and autonomic neuropathy characterized by hypotonia in infancy, variable psychomotor retardation, markedly impaired pain sensitivity with poorly healing distal ulcerations and painless fractures leading to joint deformities and amputation of fingers and toes, altered deep tendon reflexes, and dysautonomic symptoms including hypohidrosis and heat intolerance, chronic diarrhea, pupillary abnormalities, or urinary incontinence. Sensorineural hearing loss has also been reported. The severity of the disease is highly variable, with severe cases being potentially lethal in infancy.


Hereditary sensory and autonomic neuropathy type 7

A rare, genetic, periphery neuropathy characterized by a congenital insensitivity to pain, muscular hypotonia and gastrointestinal disturbances. Patients present with delayed motor milestones achievement, self-mutilations, skin ulcers, poor wound healing, painless fractures, hyperhidrosis, abdominal discomfort, diarrhea and/or constipation. Cognitive development is normal.


Hereditary sensory and autonomic neuropathy type 8

A rare autosomal recessive hereditary sensory and autonomic neuropathy characterized by congenital impaired sensation of acute or inflammatory pain in combination with an inability to identify noxious heat or cold, leading to numerous painless mutilating lesions and injuries. Further manifestations are absence of corneal reflexes resulting in corneal scarring, reduced sweating and tearing, and recurrent skin infections. Large-fiber sensory modalities such as light touch, vibration, and proprioception are normal.


Hereditary sensory and autonomic neuropathy with deafness and global delay

This syndrome is characterized by a sensory and autonomic axonal neuropathy, sensorineural hearing loss and persistent global developmental delay.

Summary:
Epidemiology
It has been described in four individuals from a consanguineous Lebanese family.
Clinical description
Onset occurred in infancy with moderate developmental delay, hypotonia and areflexia. Other less constant findings included weakness, variable dysmorphic features, unsteadiness, and optic atrophy.
Genetic counseling
Transmission appears to be autosomal recessive.

                            Last update:
                            January 2009


Hereditary sensory neuropathy-deafness-dementia syndrome

A rare genetic neurological disorder characterized by sensorineural hearing loss, sensory neuropathy, behavioral abnormalities, and dementia. Occurrence of seizures has also been reported. Age of onset is between adolescence and adulthood. The disease is progressive, with fatal outcome typically in the fifth to sixth decade.


Hereditary sodium channelopathy-related small fibers neuropathy

A rare, genetic, peripheral neuropathy disorder due to gain-of-function mutations in voltage-gated sodium channels present in the small peripheral nerve fibers characterized by neuropathic pain of varying intensity (often beginning in the distal extermities and with a burning quality) associated with autonomic dysfunction (e.g. orthostatic dizziness, palpitations, dry eyes and mouth), abnormal quantitative sensory testing, and reduction in intraepidermal nerve ﬁber density. Large fiber functions (i.e. normal strength, tendon reflexes, and vibration sense) and nerve conduction studies are typically normal.


A genetically and clinically heterogeneous group of slowly progressive neurological disorders which in the pure form is characterized by pyramidal signs (weakness, spasticity, brisk tendon reflexes, and extensor plantar responses) predominantly affecting the lower limbs and with possible association of sphincter disturbances and deep sensory loss; and in the complex form by the addition of variable neurological or non-neurological features.

Summary:
Epidemiology
The prevalence of hereditary spastic paraplegia (HSP) is highly variable, ranging from 1/11,000-77,000 in Europe.
Clinical description
Clinically, HSPs can be divided into the pure and complex form. Pure HSPs are characterized by slowly progressive lower extremity spasticity and weakness, often associated with urinary disturbances, and deep sensory abnormalities (reduction of lower extremity vibration sense). Complex forms of HSP forms are characterized by the presence of additional neurological or non-neurological features. Neurological features may include cerebellar dysfunction (ataxia, nystagmus, tremor), axonal or demyelinating peripheral neuropathy (sensory and/or motor disturbances), cognitive impairment (dysexecutive syndrome, dementia), sensory impairment (optic, auditive neuropathy), epilepsy, myopathic features (ptosis, opthalmoparesis), extrapyramidal features (Parkinsonism, chorea, dystonia), psychiatric disturbances, and brain and spine imaging abnormalities (brain white matter alterations, thin corpus callosum, brain iron accumulation, cerebellar atrophy) which may be suggestive of a genetic subtype. Non-neurological manifestations may include ophthalmological abnormalities (cataracts, retinitis pigmentosa, macular degeneration), and orthopedic abnormalities (scoliosis, joint dislocation, and different foot deformities).
Etiology
The disease is due to the dysfunction of the upper motor neurons of the corticospinal tract. To date, more than 80 genes have been linked. The encoded proteins are involved in many processes, including axonal transport, myelination, endo-membrane trafficking, mitochondria functions, complex lipid and nucleotide metabolism. The most common causative genes include SPAST (2p22.3), ATL1 (14q22.1), REEP1 (2p11.2) and KIF5A (12q.13.3) for autosomal dominant HSPs, and SPG7 (16q24.3), SPG11  (15q21.1), and CYP7B1 (8q12.3) for autosomal recessive HSP. However, a significant number of patients are without a genetic diagnosis after systematic testing.
Diagnostic methods
Diagnosis is based on the clinical symptoms, neurological examination, progressive course of the disease, biomarker dosages, brain and spine MRI, family history, molecular genetic testing, and exclusion of the differential diagnoses.
Differential diagnosis
Differential diagnosis includes multiple sclerosis, spinal vascular abnormality, vitamin B12 deficiency, HTLVI infection, primary lateral sclerosis, diplegic cerebral palsy, metabolic genetic diseases (dopa-responsive dystonia, leukodystrophies, brain metal accumulation disorders).
Antenatal diagnosis
Genetic testing is possible where a mutation has previously been identified in a family.
Genetic counseling
Patterns of inheritance include mostly autosomal dominant and autosomal recessive, and rarely X-linked and mitochondrial. In addition, multiple recessive and dominant forms exist for the genes KIF1C (17p13.2), REEP2  (5q31.2), ALDH18A1  (10q24.1), ERLIN2 (8p11.23). SPAST (2p22.3), ATL1 (14q22.1), REEP1 (2p11.2) are usually associated with the pure form, autosomal recessive forms often lead to more complicated phenotypes, while some genes are associated with both phenotypes. High intrafamilial variability and incomplete penetrance are frequent.
Management and treatment
Management is symptomatic with physiotherapy, anti-spasticity drugs (baclofen, tizanidine, diazepam, botulinum toxin), and orthoses.
Prognosis
Prognosis depends on the phenotype (pure/complex form), genotype, and is highly variable due to incomplete penetrance and variable gene expression.

                            Last update:
                            March 2019

                            - Expert reviewer(s):
                            Dr Guillaume BANNEAU  - Dr Claire EWENCZYK  - Pr Cyril GOIZET


Hereditary spherocytosis is a congenital hemolytic anemia with a wide clinical spectrum (from symptom-free carriers to severe hemolysis) characterized by anemia, variable jaundice, splenomegaly and cholelithiasis.

Summary:
Epidemiology
HS is the most common cause of inherited chronic hemolysis in North America with a prevalence of 1/5,000 births. However, osmotic fragility studies suggest the existence of extremely mild or subclinical forms, raising the prevalence to 1/2,000 in Northern Europe.
Clinical description
Jaundice is usually the first clinical manifestation in newborns (50% of cases) with anemia developing a few days after birth and requiring exchange transfusion (~10%) and transfusion support (~35%). Splenomegaly is frequently observed. Age of onset and severity vary considerably depending on the degree of anemia and hemolysis. Four HS categories have been identified: trait (normal hemoglobin (Hb), reticulocytes < 3%, bilirubin < 17micromoles/L), mild (Hb 11-15 g/dL, reticulocytes 3-6%, bilirubin 17-34 micromoles/L), moderate (Hb 8-12 g/dL, reticulocytes > 6%, bilirubin > 34 micromoles/L), and severe (Hb < 8 g/dL, reticulocytes > 10%, bilirubin > 51 micromoles/L). Aplastic crisis, often associated with viral infections, is observed in 10-15% of cases, particularly pediatric. Rare complications include poor growth, skin ulceration, chronic dermatitis, high output heart failure, and secondary iron overload.
Etiology
HS is caused by mutations in one of the following genes: SPTA1 (1q21), SPTB (14q23.3), ANK1 (8p11.21), SLC4A1 ( 17q21.31) and EPB42 (15q15-q21), that encode the red blood cell (RBC) membrane proteins erythrocytic 1 spectrin alpha chain, erythrocytic 1 spectrin beta chain, ankyrin-1, band 3 anion transport protein, and erythrocyte membrane protein band 4.2, respectively. Defects in these proteins lead to a loss in RBC membrane cohesion and membrane surface area, resulting in erythrocyte sphering, decreased deformability and premature destruction in the spleen.
Diagnostic methods
Diagnosis is based on clinical and family history, physical examination and laboratory test results. Red cell morphology, osmotic resistance, hypertonic cryohemolysis test, eosin-5-maleimide binding in flow cytometry, sodium dodecyl sulfate-poly acrylamide gel electrophoresis and ektacytometry are all used to diagnose HS. Mean cellular Hb concentration is usually above normal range (~35 g/dl), reticulocyte count normal or increased, and indirect bilirubin moderately increased. Molecular genetic testing is not routinely used to confirm diagnosis.
Differential diagnosis
Differential diagnoses include hereditary elliptocytosis, hereditary stomatocytosis, Southeast Asian ovalocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, autoimmune hemolytic anemia, and alpha-thalassemia (see these terms).
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is possible if disease-causing mutations have been identified in a family, but it is not routinely performed due to the usually mild disease course.
Genetic counseling
HS is inherited autosomal dominantly in 75% of cases. Autosomal recessive inheritance and de novo mutations have also been reported, but are less common. Genetic counseling is recommended in families with a history of HS.
Management and treatment
Treatment involves management of jaundice (phototherapy and even exchange blood transfusion to prevent hyperbilirubinemic encephalopathy) and RBC transfusions in case of severe, symptomatic anemia. Splenectomy usually results in disappearance of anemia and clear amelioration of hemolytic markers. It is not indicated in patients with HS trait, whereas it is usually necessary in severe cases, albeit delayed if possible until the age of 6 years. For intermediate categories the indication is less clear, being useful in moderate cases before puberty. Laparoscopic splenectomy is preferred if performed by experienced surgeons. A combined splenectomy and cholecystectomy may be beneficial in patients with gallstones. Pre and post-splenectomy vaccine prophylaxis and prophylactic antibiotics are recommended in order to prevent infections. Folate supplement is recommended particularly after infectious events. Serum ferritin levels should be checked annually.
Prognosis
The prognosis is variable and depends on the severity of the disease and any associated complications.

                            Last update:
                            October 2016

                            - Expert reviewer(s):
                            Dr Wilma BARCELLINI


Hereditary thermosensitive neuropathy is a rare, demyelinating, hereditary motor and sensory neuropathy characterized by reversible episodes of ascending muscle weakness, paresthesias and areflexia triggered by a febrile episode, with or without pressure palsy.


Hereditary thrombocytopenia with early-onset myelofibrosis

A rare syndromic constitutional thrombocytopenia characterized by thrombocytopenia with increased bleeding tendency (leading to epistaxis, menorrhagia, and petechiae), in combination with myelofibrosis and splenomegaly. Platelets may be abnormally large or small and partly hypo- or agranular, plasma thrombopoietin is elevated, and the number of megakaryocytes in the bone marrow increased. Additional non-hematologic manifestations have been described in some patients, including mild bone abnormalities and facial dysmorphism with large forehead, hypertelorism, deep-set eyes, and wide nostrils.


Hereditary thrombocytopenia with normal platelets

A rare, genetic, isolated constitutional thrombocytopenia disease characterized by decreased platelet counts, not associated with platelet morphology or function impairment, in multiple members of a family. Manifestations are variable, typically ranging from asymptomatic to mild bleeding diathesis (e.g. easy bruising, epistaxis, petechiae). Occasionally, a more severe bleeding tendency has been associated and a mild predisposition to infection and eczema has been reported.


Hereditary thrombophilia due to congenital antithrombin deficiency is a rare, genetic, hematological disease characterized by decreased levels of antithrombin activity in plasma resulting in impaired inactivation of thrombin and factor Xa. Patients have an increased risk for venous thromboembolism, usually in the deep veins of the arms, legs and pulmonary system and, on occasion, in other venous territories (e.g. cerebral veins or sinus, mesenteric, portal, hepatic, renal and/or retinal veins).


Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency

A rare, genetic, coagulation disorder characterized by a tendency to develop thrombosis, resulting from decreased histidine-rich glycoprotein (HRG) plasma levels. Manifestations are variable depending on location of thrombosis, but may include headaches, diplopia, progressive pain, limb swelling, itching or ulceration, and brownish skin discoloration, among others.


A rare purine metabolism disorder due to inherited deficiency of the xanthine dehydrogenase/oxidase enzyme and is characterized by very low (or undetectable) concentrations of uric acid in blood and urine and very high concentration of xanthine in urine, leading to urolithiasis.

Summary:
Epidemiology
Prevalence of hereditary xanthinuria is not known, but about 150 patients have been described so far. Annual incidence has been estimated to be between 1:6,000 and 1:69,000. These rough estimates are due to the high rate of asymptomatic cases leading to underdiagnosis and the lack of newborn screening.
Clinical description
Symptom onset may be at any age. Approximately 50 % of the patients with classical hereditary xanthinuria present with symptoms of urinary tract infection, hematuria, renal colic, acute renal failure, crystalluria or urolithiasis. In some rare patients, renal disease may evolve to renal failure, or may even induce arthropathy, myopathy or duodenal ulcer.
Etiology
Hereditary xanthinuria is due to mutations in the xanthine dehydrogenase (XDH, 2p23.1) or molybdenum cofactor sulfurase (MOCOS, 18q12.2) genes, resulting in failure to degrade hypoxanthine and xanthine to uric acid and leading to the accumulation of xanthine and, to a lesser extent, of hypoxanthine. Classical hereditary xanthinuria encompasses xanthinuria type I and II: type I is a simple xanthine dehydrogenase/oxidase deficiency, due to mutations in XDH, whereas type II results from a combined deficiency of xanthine dehydrogenase and aldehyde oxidase, due to mutations in MOCOS. Both enzymatic deficiencies lead to an identical clinical phenotype.
Diagnostic methods
Diagnosis is based on estimation of uric acid in blood and urine. If hypouricemia is confirmed, detailed purine metabolic investigation follows, and includes measurement of xanthine and hypoxanthine in urine and plasma. High urinary levels of xanthine are then typical for classical hereditary xanthinuria. In about half of patients, ultrasonography reveals the presence of xanthine urolithiasis. Additional methods for diagnostic confirmation and/or identification of the type of xanthinuria include allopurinol loading test, xanthine oxidase assay and molecular analysis.
Differential diagnosis
Hereditary xanthinuria is a clinical feature of molybdenum cofactor deficiency (see this term). The clinical picture of this disease is however much more severe, given the associated neurological damage and frequent infant death. Hypouricemia is also a biochemical marker for primary hereditary renal hypouricemia (see this term). Unlike hereditary xanthinuria, the excretion fraction of uric acid is elevated in renal hypouricemia.
Genetic counseling
Hereditary xanthinuria is an autosomal recessive disease, with a subsequent 25% recurrence risk.
Management and treatment
There is no curative treatment. Low purine diet and high fluid intake is recommended. Since the solubility of xanthine is not affected by urinary pH, alkalization is of no value. When calculi are present, a pyelolithotomy might be necessary.
Prognosis
The overall prognosis is favorable, even though, in some cases, the disease progresses to end-stage renal insufficiency.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Ivan SEBESTA  - Dr Blanka STIBURKOVA


Heritable pulmonary arterial hypertension (HPAH) is a form of pulmonary arterial hypertension (PAH, see this term), occurring due to mutations in PAH predisposing genes or in a familial context. HPAH is characterized by elevated pulmonary arterial resistance leading to right heart failure. HPAH is progressive and potentially fatal.

Summary:
Epidemiology
HPAH represent less than 4% of PAH. Prevalence is estimated at < 1/million people.
Clinical description
HPAH develop usually in adults, and rarely in children; women are twice as likely as men to be affected. Usual age at diagnosis is mid thirties. Initial symptoms include dyspnea, fatigue, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, right ventricular heave, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation.70% of patients present heart failure (classed as New York heart association functional classification (NYHA FC) III or IV).Rarely, clubbing and Raynaud phenomenon (mostly in females) have been observed. Hemoptysis has also been reported. HPAH patients have a severe clinical with less response to acute vasodilator challenge, lower cardiac index, and higher pulmonary vascular resistance. HPAH due to ACVRL1or TBX4gene mutations occurs more commonly in children with rapid progression and poor prognosis.
Etiology
HPAH has been linked to mutations in BMPR2 ((2q33) in majority of cases. However, other genes implicated in HPAH have been described in few cases, and include ACVRL1 ((12q13)), KCNK3 (2p23),CAV1(7q31), TBX4 (17q21) and SMAD9(13q12) .
Genetic counseling
Patients displaying a sporadic PAH or a PAH occurring in a familial context, should be tested in priority for mutations in BMPR2 gene. If no mutations in BMPR2gene were identified in a patient displaying a familial form of PAH, mutations in all other PAH predisposing genes have to searched successively. All PAH predisposing genes are transmitted in an autosomal dominant manner with an incomplete penetrance. In the cases ofBMPR2 mutations the penetrance is estimated to be 42% in female mutation carriers and 14% in male mutation carriers. Prenatal genetic testing and preimplantation diagnosis are considered in patients and asymptomatic relatives carriers of a mutation in PAH predisposing genes.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Barbara GIRERD  - Pr David MONTANI


Hermansky-Pudlak syndrome due to BLOC-2 deficiency

Hermansky-Pudlak syndrome without pulmonary fibrosis as a complication includes three relatively mild types (HPS-3, HPS-5 and HPS-6) of Hermansky-Pudlak syndrome (HPS; see this term), a multi-system disorder characterized by ocular or oculocutaneous albinism, bleeding diathesis and, in some cases, granulomatous colitis.

Summary:
Epidemiology
HPS-3 occurs as a genetic isolate in central Puerto Rico with a prevalence of 1/4000; additionally, around 15 non-Puerto-Rican cases of HPS-3 have been reported. Ten cases of HPS-5 have been reported and 25 cases of HPS-6, from which 20 come from an Israeli-Bedouin tribe.
Clinical description
These three types present with features of HPS including ocular or oculocutaneous albinisim, reduced visual acuity, horizontal nystagmus, easy bruising of soft tissues, epistaxis, and prolonged bleeding after dental extraction, surgery or childbirth. Women may present with medically significant menstrual bleeding. Complications of HPS may include reduced renal function and granulomatous colitis. Pulmonary fibrosis has not been found to develop in HPS-3, HPS-5 or HPS-6. The course of HPS with no pulmonary involvement is mild.
Etiology
HPS-3 is caused by mutations in the HPS3 gene (3q24), HPS-5 is caused by mutations in the HPS5 gene (11p15-p13) and HPS-6 is caused by mutations in the HPS6 gene (10q24.32). The gene products, HPS3, HPS5 and HPS6, are part of the multi-subunit complex BLOC-2 (biogenesis of lysosome-related organelles complex 2).
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr William GAHL  - Dr Marjan HUIZING


Hermansky-Pudlak syndrome due to BLOC-3 deficiency

Hermansky-Pudlak syndrome with pulmonary fibrosis as a complication includes two types (HPS-1 and HPS-4) of Hermansky-Pudlak syndrome (HPS; see this term), a multi-system disorder characterized by oculocutaneous albinism, bleeding diathesis and, in some cases, pulmonary fibrosis or granulomatous colitis.

Summary:
Epidemiology
Prevalence of all types of HPS is estimated at between 1/500,000 and 1/1,000,000 in non-Puerto Rican populations. In northwestern Puerto Rico the prevalence of HSP-1 is 1/1,800 due to a founder effect. HSP-1 is reported in sporadic patients worldwide; founder effects have (apart from Puerto Rico) also been reported in a small isolate in a Swiss village and in Japan. Prevalence of HSP-4 is unknown, but to date around 20 patients have been described worldwide.
Clinical description
HPS-1 and HPS-4 present with features of HPS including oculocutaneous albinisim, reduced visual acuity, horizontal nystagmus, easy bruising of soft tissues, epistaxis, and prolonged bleeding after dental extraction, surgery or childbirth. Women may present with medically significant menstrual bleeding. Complications of HPS may include granulomatous colitis and pulmonary fibrosis. Pulmonary fibrosis is the most serious complication of HPS-1 and HPS-4 and usually presents in the fourth or fifth decade.
Etiology
HPS-1 is caused by mutations in the HPS1 gene (10q23.1) and HPS-4 is caused by mutations in the HPS4 gene (22q11.2-q12.2). The gene products, HPS1 and HPS4, are part of the multi-subunit complex BLOC-3 (biogenesis of lysosome-related organelles complex 3).
Genetic counseling
HPS1 and HPS4 are both transmitted in an autosomal recessive manner.
Management and treatment
Lung transplant is the only known treatment for pulmonary fibrosis in HPS-1 and HPS-4. Pirfenidone may slow progression but only in patients who have significant residual lung function. Steroid therapy is not effective.
Prognosis
Prognosis is poor as the pulmonary fibrosis is fatal.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr William GAHL  - Dr Marjan HUIZING


Hermansky-Pudlak syndrome (HSP) is a multi-system disorder characterized by oculocutaneous albinism, bleeding diathesis and, in some cases, neutropenia, pulmonary fibrosis, or granulomatous colitis. HPS comprises eight known disorders (HPS-1 to HPS-8), the majority of which present with the same clinical phenotype to varying degrees of severity.

Summary:
Epidemiology
Prevalence is estimated at 1/500,000 - 1/1,000,000 in non-Puerto Rican populations. In northwestern Puerto Rico the prevalence of HPS-1 is 1/1,800.
Clinical description
HPS usually presents in early childhood, but may present at older ages, with oculocutaneous albinism (varying degrees of hypopigmentation), reduced visual acuity (often at/below the level of legal blindness), horizontal nystagmus, easy bruising of soft tissues, epistaxis, prolonged bleeding after dental extraction, surgery or childbirth and, in HPS-2 (see this term), neutropenia and recurrent infections. Women may present with medically significant menstrual bleeding. Complications may include granulomatous colitis and, in HPS-1 or HPS-4, pulmonary fibrosis (PF) (HPS with PF as a complication; see this term). PF is the most serious complication and usually presents in the fourth or fifth decade.
Etiology
HPS is characterized by a storage pool deficiency of platelets and can be caused by mutations in one of several genes: HPS1 (10q23.1), AP3B1 (5q14.1; causing HPS-2), HPS3 (3q24), HPS4 (22q11.2-q12.2), HPS5 (11p15-p13), HPS6 (10q24.32), DTNBP1 (6p22.3; HPS-7), and BLOC1S3 (19q13; HPS-8). The product of AP3B1 codes for the beta 3A subunit of adaptor complex-3 (AP-3), involved in vesicle formation and protein sorting. The function of the other HPS gene products is unknown, but they interact with each other in biogenesis of lysosome related organelle complexes (BLOCs); BLOC-3: HPS1 and HPS4; BLOC-2: HPS3, HPS5 and HPS6; BLOC-1: HPS7 and HPS8. Affected lysosome-related organelles include melanosomes in melanocytes, delta granules in platelets, lamellar bodies in pulmonary type II cells, and secretory granules in T cells.
Diagnostic methods
Diagnosis is based on clinical findings of oculocutaneous albinism in combination with a bleeding diathesis, confirmed by an absence of platelet dense bodies and genetic testing. Accurate diagnosis of the HPS subtype has important prognostic and treatment implications.
Differential diagnosis
Differential diagnoses include other forms/causes of oculocutaneous albinism, i.e., X-linked ocular albinism, Chediak-Higashi syndrome, Griscelli syndrome, Cross syndrome, pulmonary fibrosis and hemophagocytic lymphohistiocytosis.
Antenatal diagnosis
Antenatal testing may be available for families in which disease-causing mutations have been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
There is no known cure. The bleeding diathesis is a major concern during surgery, dental extraction or childbirth and may be treated with transfusion of platelets or whole blood. Desmopressin may be used prophylactically. Recombinant activated factor VII (VIIa) may also be used. Avoidance of aspirin products is essential. Sunscreen and avoidance of sunlight are important to reduce the risk of solar damage and skin malignancies. Lung transplant is the only known treatment for PF (in HPS-1, HPS-2, and HPS-4). Pirfenidone may slow the progression of PF but only in patients who have significant residual lung function. Steroid therapy is not effective. Neutropenia in HPS-2 can be treated with granulocyte-cell stimulating factor (G-CSF).
Prognosis
The course of HPS-3, HPS-5 and HPS-6 (or HPS without PF as a complication; see this term) is mild with no pulmonary involvement. Prognosis of HPS-1 and HPS-4 is poor as PF is fatal. Prognosis for HPS-7 and HPS-8 (only one case of each reported) has not been well characterized.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr William GAHL  - Dr Marjan HUIZING


A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, mild intellectual disability, seizures, obesity, and dysmorphic facial features (including large, bulbous nose, prominent philtrum, wide mouth). Additional reported features are bilateral pes planus, scoliosis, and spina bifida occulta. Brain MRI may show mild ventricular dilatation.


A rare disorder caused by infection of the central nervous system by Herpes simplex virus (HSV) that could have a devastating clinical course and a potentially fatal outcome particularly with delay or lack of treatment. This disorder often involves the frontal and temporal lobes, usually asymmetrically, resulting in personality changes, cognitive impairment, aphasia, seizures, and focal weakness.

Summary:
Epidemiology
HSVE accounts for 20 % of encephalitis cases and its annual incidence is 1/250,000-1/500,000 in industrialized nations and is presumed to be the same across the globe.
Clinical description
HSVE usually peaks in childhood (between 3 months and 6 years during primary infection with HSV-1) and in older people (bimodal distribution). The manifestations of HSVE include low-grade pyrexia accompanied by severe headache, nausea, vomiting, and lethargy, followed by neurological features, which may include cognitive dysfunction (confusion, acute memory disturbances and disorientation), behavioral changes (irritability, hallucinations, psychosis, personality changes, agitation), focal neurological abnormalities (such as focal weakness, anomia, aphasia, dysphasia,), hemiparesis and seizures. There may be marked temporal lobe edema and occasionally brainstem herniation. 20 % of HSVE cases may present a relatively mild or atypical disease.
Etiology
HSV-1 causes 90 % of cases of HSVE with 10 % of cases caused by HSV-2; the latter is a common cause in neonates (during vaginal delivery) and the immunosuppressed. HSVE results from primary infection in 1/3 of cases and reactivation in 2/3. Mutations in genes such as TLR3 (4q35) and TRAF3 (14q32.32) have been observed suggesting an influence of genetic factors, presumably by an impaired type I and type III IFN production in response to HSV-1. In 7 % of patients with HSVE, antibodies against NMDAR (N-methyl-D-aspartate receptor), may be detected. Post-HSVE, abnormal movements or relapse of symptoms may be related to these antibodies.
Diagnostic methods
The mainstay of diagnosis is detection of HSV in cerebrospinal fluid (CSF) by Polymerase Chain Reaction (PCR), although it may be negative for HSV-1 during the first 3 days of illness or after 10-14 days. CSF examination shows lymphocytosis (≥10-200/mm3) and raised protein (> or equal to 0.5-1.0 g/l). Magnetic resonance imaging findings show the characteristic abnormalities of edema and/or abnormal enhancement in one or both temporal and frontal lobes, the insular cortex, and the angular gyrus.
Differential diagnosis
Differential diagnosis includes: other viral causes of encephalitis, (varicella zoster virus, enteroviruses etc); bacterial infections, including ricketsial disease, mycoplasma pneumonia, chlamydophila infections; autoimmune diseases, such as paraneoplastic limbic encephalitis, acute disseminated encephalomyelitis, Rasmussen subacute encephalitis; and other causes including space occupying lesion and non-infectious encephalopathy.
Genetic counseling
HSVE occurs sporadically.
Management and treatment
The mainstay of treatment is intravenous injection (IV) of acyclovir (10mg/kg) 3 times daily for 14 days-21 days. CSF examination could be repeated at the end of that period to check if the virus has been cleared. Dosage should be adjusted in cases of renal malfunction. In immunocompromised patients, acyclovir should be continued for at least 21 days. Corticosteroids such as dexamethasone have been used in patients with HSVE, but the benefits are uncertain. The beneficial effects of methylprednisolone in children with antibodies against the NMDAR have yet to be established, as well as the possible benefits of steroid therapy or oral valacyclovir following IV acyclovir.
Prognosis
If untreated, mortality rates are 70 % that can be reduced to 28% following treatment. However morbidity remains high and survivors often have residual deficit such as chorea or epilepsy. A delay of 48 hours or more in starting acyclovir is associated with poor outcome.

                            Last update:
                            June 2015

                            - Expert reviewer(s):
                            Dr Jeoffrey SEGURA  - Pr Tom SOLOMON


Herpes simplex (HSV) stromal keratitis is an infectious ocular disease of either necrotizing or non-necrotizing form, due to an HSV infection, and characterized by corneal stromal necrosis, inflammation, ulceration and infiltration by leukocytes. Corneal perforation and blindness can also occur in severe cases.


A rare superficial pemphigus disease characterized by severe intractable pruritus with erythematous or urticarial plaques and sometimes vesicles organized in a herpetiform pattern. Mucosae are generally spared. Eosinophilia in peripheral blood and low titers of circulating autoantibodies are observed in many cases. Histology can show an aspect of either pemphigus (superficial or deep), or an intraepidermal infiltrate rich in eosinophils (eosinophilic spongiosis).


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by profound intellectual disability, hypotonia, coarse facial features, strabismus and impaired visual fixation, hypermobility of interphalangeal joints, contractures in the elbow joints, and pes planovalgus. Seizures and episodes of aggressive behavior during sleep have also been reported.


Hidrotic ectodermal dysplasia, Christianson-Fourie type is a rare ectodermal dysplasia syndrome characterized by tricho- and onychodysplasia in association with cardiac rhythm abnormalities. Patients present with sparse scalp hair and eyelashes, absent or sparse eyebrows, dystrophic thickened nails (on fingers distal end may be lifted from the nail bed) and supraventricular tachicardia or sinus bradicardia.


Hidrotic ectodermal dysplasia, Halal type is a form of ectodermal dysplasia syndrome (see this term) characterized by trichodysplasia, with absent eyebrows and eyelashes, onychodysplasia, mild retrognathia, abnormal dermatoglyphics (excess of whorls on fingertips, radial loop on finger, hypothenar pattern), intellectual disability and normal teeth and sweating. Additional variable manifestations include high implanted or prominent ears, mild hearing loss, supernumerary nipple, café-au-lait spots, keratosis pilaris, and irregular menses. To date, four individuals from 2 generations of a consanguineous family of Portuguese descent have been described in the literature. Males and females were equally affected. Hidrotic ectodermal dysplasia, Halal type is inherited in an autosomal recessive manner.


Clouston syndrome (or hidrotic ectodermal dysplasia) is characterised by the clinical triad of nail dystrophy, alopecia, and palmoplantar hyperkeratosis.

Summary:
Epidemiology
The disease was first described in the French-Canadian population (in which it is associated with a founder effect), but has since been identified in several other ethnic groups. The exact prevalence is unknown and the syndrome is likely to be underdiagnosed.
Clinical description
Nail abnormalities are the most consistent feature and frequently manifest at birth or in early infancy. The nails are thickened, slow growing, brittle, often hyperconvex and discoloured with striation. Additional reported features include micronychia, onycholysis and recurrent paronychial infections leading to nail loss. Hair involvement manifests at birth or later during infancy or childhood, and ranges from total to partial, often progressive, alopecia. Residual scalp hair is slow growing, sparse, fine and brittle. Eyebrows and eyelashes are also frequently sparse and axillary, pubic and body hair can be affected. Palmoplantar hyperkeratosis is not a constant finding. When present, it usually begins in childhood and tends to worsen with age; some patients also develop hyperkeratosis and hyperpigmentation over the joints and bony prominences. The teeth are usually unaffected and sweating is normal.
Etiology
Clouston syndrome is caused by mutations in the GJB6 gene (13q12), encoding the gap junction protein connexin 30 (Cx30).
Diagnostic methods
Diagnosis may be suspected on the basis of the clinical triad of nail dystrophy, hypotrichosis and hyperkeratosis of the palms and soles. The diagnosis can be confirmed by molecular analysis of the GJB6 gene.
Differential diagnosis
The differential diagnosis should include pachyonychia congenita and other forms of ectodermal dysplasia (see these terms).
Antenatal diagnosis
Prenatal testing is possible in families where the disease-causing mutation has been identified.
Genetic counseling
Clouston syndrome is transmitted as an autosomal dominant trait. Disease penetrance is complete, but expression is quite variable even between affected individuals from the same family.
Management and treatment
At present there is no treatment for the disease and management is purely supportive.
Prognosis
The life-span for patients is normal.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


A rare pulmonary condition characterized by non-cardiogenic pulmonary edema occurring in otherwise healthy individuals within days of an ascent above 2500-3000 m. Early symptoms include exertional dyspnea, non-productive cough, chest tightness, and reduced exercise performance, followed by dyspnea at rest and possibly orthopnea, as well as gurgling in the chest and pink frothy sputum in advanced cases. Clinical signs are cyanosis, tachypnea, tachycardia, crackles or wheezing, and elevated body temperature (generally not exceeding 38.5°C). Signs of concomitant high-altitude cerebral edema may also be observed. Chest x-rays typically show patchy opacities predominantly in the right middle lobe.


High bone mass osteogenesis imperfecta is a rare, genetic, primary bone dysplasia disorder characterized by increased bone fragility, manifesting with multiple, childhood-onset, vertebral and peripheral fractures, associated with increased bone mass density on radiometric examination. Patients typically present normal or mild short stature and dentinogenesis, hearing, and sclerae are commonly normal.


High grade B-cell lymphoma with MYC and/ or BCL2 and/or BCL6 rearrangement

A rare aggressive B-cell non-Hodgkin lymphoma characterized by a rearrangement in MYC and BCL2 and/or BCL6 (so-called double-hit or triple-hit lymphoma). The category includes double-hit cases with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, blastoid cases with a double-hit, and cases with a DLBCL, not otherwise specified, morphology with a double-hit. It refers only to de novo cases, not to lymphomas with a history of pre-existing or coexistent indolent lymphoma. Patients typically present with widespread disease, including involvement of lymph nodes, bone marrow, and central nervous system.


High myopia-sensorineural deafness syndrome is a rare genetic disease characterized by high myopia, typically ranging from -6.0 to -11.0 diopters, and moderate to profound, bilateral, progressive sensorineural hearing loss with prelingual-onset. Affected individuals do not present other systemic, ocular or connective tissue manifestations.


High-grade neuroendocrine carcinoma of the cervix uteri is a rare, aggressive, primary cervical neoplasm, originating from neuroendocrine cells present in the lining epithelium of the cervix, characterized, macroscopically, by usually large lesions, sometimes with a barrel-shaped appearance. Patients often present with abnormal vaginal bleeding or discharge, pelvic/abdominal pain, post-coital spotting and/or dysuria, while symptoms related to carcinoid syndrome are not frequent.


High-grade neuroendocrine carcinoma of the corpus uteri is an extremely rare, aggressive, primary uterine neoplasm, originating from neuroendocrine cells scattered within the endometrium, characterized, macroscopically, by a bulky, frequently polypoid, mass with abundant necrosis located in the uterus and, histologically, by rosette-like and cord-like structures consisting of small, rounded cells with oval nuclei and scarce cytoplasm. Patients often present with dysfunctional uterine bleeding, pelvic or abdominal mass and, especially in later stages of the disease, abdominal pain. Symptomatic metastatic spread or symptoms related to a paraneoplastic syndrome, such as retinopathy, or Cushing syndrome due to ectopic ACTH production, may be associated.


Hinman syndrome (HS) or non-neurogenic neurogenic bladder is a voiding dysfunction of the bladder of neuropsychological origin that is characterized by functional bladder outlet obstruction in the absence of neurologic deficits.

Summary:
Epidemiology
Prevalence is not known.
Clinical description
The syndrome typically occurs in early to late childhood but some adult cases have been observed. It typically manifests at some point after toilet training in early to late childhood. Patients present with enuresis, urgent voiding with incontinence, infrequent voiding, intermittency, straining, urinary tract infections and diffuse abdominal pain.
Etiology
The syndrome is probably caused by acquired behavioral and psychological disorders manifested by bladder dysfunction mimicking neurologic disease. The dysfunction is associated with abnormal family dynamics in 50% of cases. Individuals under psychosocial pressure try to inhibit enuresis by voluntarily contracting the external sphincter. These voluntary contractions lead to an obstruction of the urinary tract, characterized by an intermittent stream, increased residual urine and increased intravesicular pressure. The resultant destruction of the urinary tract simulates true neurogenic bladder.
Diagnostic methods
Diagnosis is based on the presence of the clinical and radiographic manifestations of neurogenic bladder in the absence of an underlying neurogenic abnormality. The diagnosis of HS should be considered at uroradiography in any child with unexplained bladder trabeculations, residual urine, incontinence or posterior urethral distention. The observation of posterior urethral distention following voluntary contraction of the external sphincter using a voiding cystourethrogram is suggestive of the condition.
Differential diagnosis
Differential diagnoses include neurogenic bladder, enuresis and urinary tract infection. HS can be differentiated from neurogenic bladder by five criteria: a) intact perineal sensation and anal tone, b) normal anatomy and function of the lower extremities, c) absence of skin lesions overlying the sacrum, d) normal lumbosacral spine at plain radiography, and e) normal spinal cord and magnetic resonance imaging (MRI). It is important to distinguish between true neurogenic bladder and HS because true neurogenic bladder requires surgery.
Management and treatment
Treatment for HS focuses on helping the child void normally through alleviating psychosocial pressures which are likely to be causing the problem with voiding through suggestion therapy including hypnosis, bladder retraining and timed voiding. Catheterization may be used if the bladder does not empty completely and if the bladder has uninhibited contractions. Antispasmodic drugs may be of benefit. Occasionally external sphincterotomy is required.
Prognosis
HS can result in trabeculated bladder, ureterovesical obstruction, dilation of the upper tracts and renal damage and is often associated with urinary tract infections. However, improvements in patients with HS have been seen with bladder retraining and suggestion therapy.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                             Pierre CLAUDON


A primary bone dysplasia, characterized by premature degenerative arthropathy of the hip. The disease presents with hip joint discomfort/pain and gait disturbances that usually develop in childhood and that progress to severe functional disability and limited mobility by early adulthood. Involvement of the vertebral bodies and other joints is minimal, height is not significantly reduced, and general health is unimpaired. Radiographically, the femoral heads are flattened and irregular and degenerative osteoarthritis develops in the hip joints, as evidenced by the presence of periarticular cysts, sclerosis, and joint space narrowing.


Hirschsprung disease-deafness-polydactyly syndrome is an extremely rare malformative association, described in only two siblings to date, characterized by Hirschsprung disease (defined by the presence of an aganglionic segment of variable extent in the terminal part of the colon that leads to symptoms of intestinal obstruction, including constipation and abdominal distension), polydactyly of hands and/or feet, unilateral renal agenesis, hypertelorism and congenital deafness. There have been no further descriptions in the literature since 1988.


A rare, genetic, developmental defect during embryogenesis syndrome characterized by total or partial colonic aganglionosis associated with peripheral, usually multifocal, neuroblastic tumors (ganglioneuroblastoma, neuroblastoma, ganglioneuroma). Congenital central hypoventilation syndrome, with variable severity of respiratory compromise, cardiovascular and ophthalmologic symptoms, consistent with autonomic nervous system dysfunction, is occasionally associated.


Hirschsprung disease-nail hypoplasia-dysmorphism syndrome is a fatal malformative disorder that is characterized by Hirschsprung disease, hypoplastic nails, distal limb hypoplasia and minor craniofacial dysmorphic features (flat facies, upward slanting palpebral fissures, narrow philtrum, narrow, high arched palate, micrognathia, low set ears with abnormal helices). Hydronephrosis has also been reported. There have been no further descriptions in the literature since 1988.


Hirschsprung disease-type D brachydactyly syndrome is characterized by Hirschsprung disease and absence or hypoplasia of the nails and distal phalanges of the thumbs and great toes (type D brachydactyly). It has been described in four males from one family (two brothers and two maternal uncles). Transmission appears to be X-linked recessive but autosomal dominant inheritance with incomplete penetrance in females can not be ruled out.


A rare congenital intestinal motility disorder that is characterized by signs of intestinal obstruction due to the presence of an aganglionic segment of variable extent in the terminal part of the colon.

Summary:
Epidemiology
Hirschsprung disease (HSCR) has an estimated prevalence at birth of 1/5,000-10,000 worldwide. In rectosigmoid HSCR, there is a male predominance of 4:1.
Clinical description
HSCR generally manifests shortly after birth with symptoms of lower intestinal obstruction such as failure to pass meconium within the first 48 hours of life, abdominal pain, constipation, progressive abdominal distention, vomiting, and occasionally diarrhea. Rarely, it presents later in childhood with symptoms of severe constipation and failure to thrive. Four forms of the disease are recognized on the basis of the extent of aganglionosis: in the classic form (HSCR; 80% of cases), aganglionosis is restricted to the rectosigmoid. In long-segment HSCR (15%), aganglionosis extends above the sigmoid colon, while in total colonic aganglionosis (5%), aganglionosis involves the entire large intestine. Total intestinal aganglionosis is the most severe form and is extremely rare.
Etiology
HSCR is a neurocristopathy and is due to a defect in the development of the enteric nervous system. It is characterized by the absence of neuronal ganglion cells (aganglionosis) in the terminal part of the intestine. The affected bowel segment maintains a state of tonic contraction, resulting in a functional bowel obstruction. Genetic and environmental factors play a role in its pathogenesis. Several genes are associated with HSCR, particularly: the RET proto-oncogene (RET; 10q11.21), the glial cell derived neurotrophic factor gene (GDNF), the neurturin gene (NRTN), the endothelin B receptor gene (EDNRB), the endothelin-3 gene (EDN3), the endothelin-converting enzyme 1 gene ECE1, and the L1 cell adhesion molecule gene L1CAM.
Diagnostic methods
Diagnosis is based on suction rectal biopsy of rectal mucosa and submucosa that shows aganglionosis, thickened extrinsic nerve fibers and overexpression of acetylcholinesterase. Recently, it has been shown that calretinin immunohistochemistry is useful. Assessment for associated anomalies allows the detection of syndromic HSCR. Plain abdominal radiography, lower gastrointestinal contrast studies, and ultrasound are useful in excluding alternative diagnoses.
Differential diagnosis
Differential diagnosis includes gastrointestinal malformations such as anorectal malformation, chronic intestinal pseudo-obstruction, meconium ileus, anorectal stenosis and pelvic tumors. HSCR can also be associated with syndromes such neurologic Waardenburg-Shah syndrome, Bardet-Biedl syndrome, Mowat-Wilson syndrome, Haddad syndrome, or multiple endocrine neoplasia syndrome type 2A, Goldberg Shprintzen syndrome, Smith-Lemli-Opitz syndrome, Kaufman-McKusick syndrome, orofaciodigital syndrome type 5, PCWH syndrome, cartilage-hair-hypoplasia, and Down syndrome.
Antenatal diagnosis
There are currently no practical capabilities for the prenatal diagnosis of HSCR, as abnormal sonographic findings are absent in the majority of fetuses with HSCR.
Genetic counseling
Most cases of non-syndromic HSCR are sporadic although familial cases are possible and thus genetic testing of both parents and the index patient may give a more accurate estimation of the risk of recurrence in future pregnancies. Genetic testing of RET to exclude the rare possibility of a MEN 2A associated RET mutation should be considered.
Management and treatment
Treatment is surgical. It consists in resection of the aganglionic segment together with the transition zone followed by anastomosis of the proximal bowel to the anal margin. Different techniques including minimal invasive surgery as well as transanal surgery are applied. Type of surgery is dependent on the patient, length of aganglionosis and preference of the surgeon. Small bowel aganglionosis can lead to intestinal failure. In case of total intestinal aganglionosis, intestinal transplantation may be required.
Prognosis
Overall survival and functional prognosis are good in rectosigmoid or long-segment Hirschsprung, despite issues with constipation and continence even following surgical correction. Functional prognosis of total colonic Hirschsprung's is acceptable. The prognosis for children with small bowel or total intestinal aganglionosis leading to intestinal failure can be poor although intestinal transplantation is attempted to offer long term survival in complicated cases. Hirschsprung enterocolitis occurs in 30-50% of the cases but reacts well to treatment in most cases.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr A.S. [Alice] BROOKS | ERNICA* - Pr Mikko PAKARINEN | ERNICA* - Dr Pim SLOOTS | ERNICA* - Pr Tomas WESTER | ERNICA*

                                * European Reference Network


His bundle tachycardia is a very rare congenital genetic tachyarrhythmia characterized by incessant tachycardia and high morbidity and mortality.


Histidinemia is a rare metabolic disorder characterized by elevated histidine levels in blood, urine, and cerebrospinal fluid, generally with no clinical repercussions.

Summary:
Epidemiology
Reported prevalence varies widely from 1/8,600 to 1/180,000, probably as a result of differing screening programs.
Clinical description
Histidinemia is defined biochemically as elevated histidine in blood, urine and cerebrospinal fluid, and decreased levels of the metabolite urocanic acid in blood, urine, and the skin. In most individuals with histidinemia, the condition is clinically silent and considered benign, with no need for treatment or a specific diet. In a small subset of patients with specific events in the neonatal period, such as low oxygen, it has been suggested that histidinemia may contribute to development of intellectual disability, behavioral or learning disorders. Growth is normal in patients with the disorder. Histidinemia is important because in the 1960s and 1970s the condition was unnecessarily added to universal newborn screening before the natural history was fully understood.
Etiology
Histidinemia is caused by impaired conversion of histidine to urocanic acid via the histidase enzyme. Deficiency in this enzyme is related to mutations in the histidine ammonia-lyase HAL gene (12q22-q24.1).
Diagnostic methods
The disease can be diagnosed with blood and urine tests. Nano optical probe samarium tetracycline can be used. The diagnosis can be confirmed by demonstrating the absence or marked reduction of histidase activity in skin or the absence of urocanic acid in skin.
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
Restricting dietary histidine brings the blood histidine level back to normal and eliminates the urinary imidazole metabolites in patients with histidinemia and urocanase deficiency. However, no urgent treatment is required because of the benign nature of this condition.
Prognosis
The life expectancy is not affected. Patients with histidinemia show good prognosis.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Dr Jeffrey BROSCO


Histidinuria-renal tubular defect syndrome

A rare disorder of histidine metabolism characterized by histidinuria without histidinemia due to impaired intestinal and renal tubular absorption of histidine. Developmental delay, intellectual disability, seizures, and mild dysmorphic features have been reported in association. There have been no further descriptions in the literature since 1992.


A rare histiocytic tumor characterized by a malignant proliferation of cells showing morphological and immunophenotypic features of mature tissue histiocytes. Most cases occur in extranodal sites, most commonly the intestinal tract, skin, and soft tissue. Patients may present with a solitary mass, lymphadenopathy, a skin rash or numerous tumors on the trunk and extremities, lytic bone lesions, hepatosplenomegaly with pancytopenia, intestinal obstruction, and/or systemic symptoms. The neoplasm is aggressive with typically poor therapy response.


A rare arrhythmogenic disorder characterized by cardiomegaly, severe cardiac arrhythmias or sudden death, and the presence of histiocyte-like cells within the myocardium.

Summary:
Epidemiology
Approximately 100 patients have been described in the literature to date. There is a female predominance with a female:male ratio between 3:1 to 4:1.
Clinical description
The majority of reported cases involve children under 2 years of age, indeed histiocytoid cardiomyopathy is a disease of infancy and early childhood. Clinically, the disease may manifest as various types of incessant arrhythmia (including atrial and ventricular fibrillation, supraventricular and ventricular tachycardia and Wolff-Parkinson-White syndrome) but sudden death due to cardiac arrest is a common presentation (20%). Lethal arrhythmias might be triggered by fever. Association with other cardiac defects (ventricular and atrial septal defects, hypoplastic left heart syndrome, endocardial fibroelastosis and left ventricle noncompaction) and with extracardiac anomalies (hypotonia, MIDAS syndrome, Peters anomaly, and congenital glaucoma) has also been reported in 16 and 17% of cases respectively.
Etiology
Etiology of histiocytic cardiomyopathy remains unknown. It was largely suspected to be caused by a developmental anomaly of the conduction system; however, genetic testing support various molecular basis. Mutation in cytochrome b, as well as A8344G mitochondrial DNA mutation have been described but seem to be sporadic variants. Whole Genome Expression Analysis support cluster of candidate gene at 1q21.3c, 2q12.1a and a decrease in copy number of the genes encoding S100A calcium binding protein, along with a strong decrease in interleukin 33 expression.
Diagnostic methods
Histiocytoid cardiomyopathy is suspected on the basis of clinical presentation, electrocardiogram, echocardiography, cardiac magnetic resonance imaging, myocardial biopsy or at autopsy. Unfortunately diagnosis is, typically post-mortem by histological evaluation, findings are pathognomonic for the disease and include yellow-tan nodules in the myocardium and, in some cases, in the subendocardial and subepicardial areas. The nodules are composed of nests of foamy histiocyte-like cells with a granular cytoplasm containing lipid droplets and abundant atypical mitochondria. These abnormal myocytes are found mainly in the ventricles but involvement of the valves has also been reported.
Differential diagnosis
As sudden infant death is frequently the presenting manifestation, sudden infant death syndrome (SIDS) is often the initial diagnosis in these cases but can be ruled out by histological evaluation of the myocardial tissue.
Genetic counseling
There is a familial tendency of 5%; however, mode of inheritance (X-linked dominant inheritance and autosomal recessive) is still debated. Female predominance is not understood.
Management and treatment
Management options for patients presenting with arrhythmias include surgical removal of the nodular lesions, electrophysiological mapping and radiofrequency ablation of the arrhythmias. Heart transplantation have been proposed for few patients. Antiarrhythmics are generally ineffective but one patient showed a good response to treatment with amiodarone.
Prognosis
The prognosis in general is poor and the disease is usually fatal.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Alice MALTRET


A rare mycosis characterized by granulomatous inflammation primarily of the lung after inhalation of spores of Histoplasma capsulatum. The severity of clinical disease depends on the immune status of the individual and the size of the inoculum. In immunocompetent persons, the infection usually takes a self-limiting and asymptomatic or relatively mild, flu-like course. In immunocompromised patients, it can become progressive and disseminated, involving multiple organs and presenting with fever, pneumonia, hepatosplenomegaly, skin infiltrates, and endocarditis, among others.


A rare neoplastic disease characterized by occurrence in association with human immunodeficiency virus (HIV) infection. Kaposi sarcoma, aggressive B-cell lymphomas, and invasive cervical cancer are considered AIDS-defining cancers, while a variety of other cancers are known to be related to HIV, including Hodgkin lymphoma, hepatocellular carcinoma, and lung, anal, oral cavity and oropharyngeal, vulvar, and penile cancer. The majority of cancers in AIDS patients are associated with co-infection with oncogenic viruses, such as Epstein-Barr virus, human herpesvirus 8, and human papillomavirus.


An early-onset and most severe form of rare hemochromatosis characterized by the usual features of hemochromatosis accompanied by cardiomyopathy and hypogonadism.

Summary:
Epidemiology
Less than 100 reported cases were reported with a broad geographical distribution. Both sexes are equally affected.
Clinical description
Age of onset is usually less than 30 years. This juvenile form of hemochromatosis has the classical features of symptomatic HC but is also characterized by severe cardiomyopathy and hypogonadism. Arthropathy, hepatic fibrosis, glucose intolerance, and increased skin pigmentation are frequent. Biochemical abnormalities include elevated serum iron, transferrin saturation and ferritin.
Etiology
Two types of the disease have been described, both being transmitted in an autosomal recessive way. The most frequent form is caused by mutations in the hemojuvelin (HJV) gene on chromosome 1 and the second form is caused by mutations in the hepcidin (HAMP) gene on chromosome 19. These mutations result in complete or major hepcidin deficiency, thus increasing drastically duodenal iron absorption and iron release from the spleen.
Diagnostic methods
Diagnosis is based on biochemical testing for serum transferrin saturation (>90%), serum ferritin concentration (often >2000 microg/L), and on magnetic resonance imaging (MRI) for quantifying visceral (especially hepatic and cardiac) iron overload. Molecular genetic blood testing allows, in most cases, to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes TFR2-related hemochromatosis and post-transfusional iron overload in the case of hematological diseases such as thalassemia major, sickle cell disease, and other rare anemias.
Genetic counseling
Genetic counseling should be offered to first-degree relatives of patients with genetically confirmed HJV or HAMP-related hemochromatosis. Particular focus should be given to siblings as they are at the highest risk (25%).
Management and treatment
Intensive phlebotomies, sometimes combined with iron chelation therapy, form the basis of treatment.
Prognosis
Complications like heart failure are often fatal. Early and intensive iron depletive therapy can significantly improve an otherwise devastating prognosis.

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Pr Graça PORTO | EuroBloodNet*

                                * European Reference Network


HNF1B-related autosomal dominant tubulointerstitial kidney disease

A form of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to variants in or whole gene deletions of HNF1B, which is characterized by chronic tubulo-interstitial nephritis, that manifests with nonsignificant urinalysis and slowly progressive renal failure. It can be associated with cystic kidney dysplasia, early onset diabetes and extrarenal manifestations.

Summary:
Epidemiology
ADTKD is estimated to account for approximately 2-5% of monogenic causes of chronic kidney disease. The prevalence of HNF1B-related ADTKD is unknown.
Clinical description
HNF1B-related ADTKD is a congenital disorder of kidney development and can manifest as early as in the prenatal period with large and hyperechogenic kidneys. Postnatally, tubulointerstitial kidney disease with or without bilateral cystic kidney dysplasia can be apparent. Chronic renal insufficiency generally has a slow-progressive course; however, some infants present with early manifestation of end-stage kidney disease (ESKD). Additional malformations of the genitourinary tract are diagnosed in the antenatal or immediate postnatal period. In most patients, hypomagnesemia, hyperuricemia, elevated liver enzymes and maturity onset diabetes of the young manifest later during the clinical course (e.g. in school-aged children, adolescents or young adults). Due to the phenotypic overlap with 17.2q microdeletion syndrome, it is currently unclear if HNF1B-related ADTKD is also associated with neuropsychiatric symptoms.
Etiology
HNF1B-related ADTKD is caused by heterozygous variants in the human transcription factor 2 gene (HNF1B; 17q12) or large heterozygous deletions of 17q12 including HNF1B and a large number of additional genes. HNF1B encodes for hepatocyte nuclear factor-1 beta (HNF-1 beta), a transcription factor that is expressed early in embryonic development. HNF-1 beta acts as a homo- or heterodimer with HNF-1 alpha and plays a key role for tissue-specific regulations of gene expression in various organs such as kidneys, liver, biliary ducts, pancreas and the urogenital tract. However, it must be noted that HNF1B variants are associated with a spectrum of clinical phenotypes ranging from renal dysplasia, multicystic dysplastic kidney and other congenital anomalies of kidneys and urinary tract (CAKUT).
Diagnostic methods
Diagnosis may be difficult due to the heterogenous picture associated with HNF1B variants or gene deletions. Renal biopsy confirms a picture of interstitial fibrosis and tubular atrophy; however, renal ultrasound followed by genetic gene panel testing is the gold standard of diagnostic procedures.
Differential diagnosis
Differential diagnosis is complex, as the disease may mimic a variety of renal disorders. The clinical picture is shared with other forms ADTKD (UMOD-, MUC1-, REN-related). Other cystic kidney diseases (e.g. ARPKD, ADPKD, and other ciliopathies) may also present with renal ultrasound images similar to ADTKD-HNF1B. In 17.2q microdeletion syndrome, neurological involvement is possible in patients initially presenting with the kidney phenotype.
Antenatal diagnosis
Prenatal diagnosis is possible by fetal ultrasound or where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal dominant with de novo variants or gene deletions in about 50% of cases. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. However, there is variable intrafamilial expression and it should be noted that HNF1B is associated with a variable degree of renal insufficiency.
Management and treatment
Treatment is symptomatic and interdisciplinary, requiring pediatric nephrologists and diabetologists. Chronic renal disease and diabetes are treated according to international standards. Hypomagnesemia can be managed with magnesium supplementation; hyperuricemia with allopurinol in severe cases. Gene therapy is currently not available.
Prognosis
The prognosis is largely dependent on renal function and sufficient treatment of diabetes at later ages. When kidney transplantation is required, there is no risk of recurrence after transplantation. However, when using steroids and calcineurin inhibitors, especially tacrolimus, there is an enhanced risk of post-transplant diabetes.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Pr Stefanie WEBER


HNRNPDL-related limb-girdle muscular dystrophy D3

A rare, mild subtype of autosomal dominant limb-girdle muscular dystrophy characterized by a typically adult onset of mild, progressive, proximal weakness of pelvic and shoulder girdle muscles and progressive, permanent finger and toes flexion limitation without flexion contractures. Normal to highly elevated creatine kinase serum levels are observed.


Hodgkin lymphoma (HL) is a heterogeneous group of malignant lymphoid neoplasms of B-cell origin characterized histologically by the presence of Hodgkin and Reed-Sternberg (HRS) cells in the vast majority of cases.

Summary:
Epidemiology
HL is an uncommon cancer with an incidence of about 1/40,000 in North America and Europe. There are about 8500 new cases reported in the U.S. each year.
Clinical description
HL is comprised of 2 major forms: classical Hodgkin lymphoma (CHL; see this term), seen in 95% of all HL cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL; see this term), seen in only 5% of all HL cases. Disease onset occurs most frequently in young adults (age 15-35) followed by older adults (over the age of 55) and usually begins with the painless swelling of a lymph node in the upper body. Disease can spread to multiple lymph node regions or lymphoid structures and associated systemic symptoms (weight loss > 10% of baseline, fevers, night sweats) are observed in about 20% of patients.
Etiology
The exact cause is unknown but immunological, genetic and environmental factors are thought to be involved.
Management and treatment
Treatment with radiotherapy and systemic chemotherapy leads to a very good prognosis. Follow-up physical exams, blood tests and x-rays are needed to check for recurrence and check for any long-term side effects of the toxic treatments. Possible long-term side effects include secondary cancers, infertility, reduced immunity, thyroid problems, heart disease and stroke.
Prognosis
The international prognostic score (IPS) is a score given based on the presence of 7 risk factors (male sex, >45 years of age, stage 4 disease, serum albumin <4g/dl, hemoglobin <10.5 g/l, lymphocytopenia and WBC count >15,000/mm3) at the time of diagnosis. The more factors present, the less favorable the prognosis. The cure rates are 90% for early-stage HL and 70% for advance stage HL.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Joseph CONNORS


A rare ophthalmic disorder characterized by the unilateral or bilateral occurrence of a tonic pupil (showing sectorial denervation of the sphincter pupillae, so that the pupil constricts poorly to light, while the response to near is present but abnormally prolonged), in association with the absence of deep tendon reflexes. In some patients, patchy hypo- or anhidrosis may also be present (a variant known as Ross syndrome). The condition typically occurs in young adults, with a female preponderance.


A rare, early-onset and life-threatening, multiple carboxylase deficiency that when left untreated, is characterized by vomiting, tachypnea, irritability, lethargy, exfoliative dermatitis, and seizures that can worsen to coma and death.

Summary:
Epidemiology
The exact prevalence of holocarboxylase synthertase deficiency (HCSD) is unknown, but the condition is one of the rarest inborn errors of metabolism. Prevalence at birth is estimated to be less than 1/200,000.
Clinical description
Clinical onset is usually within hours, days or weeks of birth, although it may occur during infancy or early childhood. Individuals with the disorder usually exhibit poor appetite, vomiting, lethargy, irritability, hypotonia and exfoliative dermatitis. Metabolically, they have ketolactic acidosis, organic acidemia (-uria) and hyperammonemia. Without treatment, affected infants may progress to intractable seizures, cerebral edema and coma. These children often develop growth and developmental delays.
Etiology
HCSD is caused by mutations in the HLCS gene (21q22.1) resulting in reduced holocarboxylase synthetase (HCS) activity. This enzyme is important in covalent binding of biotin to the various biotin-dependent carboxylases that require the vitamin for activity. Failure to attach the biotin results in multiple carboxylase deficiency and accumulation of various, specific abnormal organic acids.
Diagnostic methods
Some affected individuals are identified through newborn screening by demonstration of abnormal organic acids, consistent with multiple carboxyalse deficiency. Diagnosis is based on clinical signs and typical organic acid abnormalities. Diagnosis can be confirmed by enzyme activity assays in leukocytes or fibroblast extracts, or by mutation analysis.
Differential diagnosis
Based on organic acids, conditions to be considered in the differential diagnosis include biotinidase deficiency and isolated carboxylase deficiencies. Other conditions to be consider include urea cycle defects (based on presence of hyperammonemia) and sepsis and other inborn errors of metabolism (based on neurological compromise and seizures in the neonatal period).
Antenatal diagnosis
Prenatal diagnosis can be performed by organic acid analysis by stable isotope dilution techniques in amniotic fluid, enzymatic determination of HCS activity in amniocytes, or mutation analysis on DNA from chorionic villus biopsy or amniocentesis.
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 of the 25% risk of having an affected child for each pregnancy.
Management and treatment
The primary treatment for HCSD is free biotin supplementation which can improve the clinical status of symptomatic individuals with the enzyme deficiency and prevent some or all symptoms from developing in asymptomatic individuals with the disorder. Treatment should be started as soon as possible after diagnosis and must be continued lifelong. Affected individuals should be monitored for later-onset complications and for compliance with therapy. Timely and ongoing treatment makes it possible to reduce symptoms considerably, although some patients develop complications despite appropriate treatment often requiring higher doses of biotin.
Prognosis
In the absence of early diagnosis and treatment, mortality is high. Morbidity in surviving affected individuals depends on the time of diagnosis and on the degree of damage related to metabolic crises.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Dr Barry WOLF


Holoprosencephaly-caudal dysgenesis syndrome is a central nervous system malformation syndrome characterized by holoprosencephaly with microcephaly, abnormal eye morphology (hypotelorism, cyclopia, exophthalmos), nasal anomalies (single nostril or absent nose), and cleft lip/palate, combined with signs of caudal regression (sacral agenesis, sirenomelia with absent external genitalia).


Holoprosencephaly-craniosynostosis syndrome is a rare developmental defect during embryogenesis syndrome characterized by the association of primary craniosynostosis (usually involving the coronal and metopic sutures) with holoprosencephaly (ranging from alobar to, most commonly, semilobar) and various skeletal anomalies (typically, hand and feet anomalies including fifth digit clinodactyly, hypoplastic phalanges and cone-shaped epiphyses, small vertebral bodies, scoliosis, coxa valga and/or flexion deformities of hips). Craniofacial asymmetry, microcephaly, brachy/plagiocephaly, short stature and psychomotor delay are additional common features.


Holoprosencephaly-postaxial polydactyly syndrome associates, in chromosomally normal neonates, holoprosencephaly, severe facial dysmorphism, postaxial polydactyly and other congenital abnormalities, suggestive of trisomy 13 (see this term).

Summary:
Epidemiology
Incidence is unknown.
Clinical description
Dysmorphic features include hypotelorism, severe eye anomalies such as microphtalmia or anophtalmia, premaxillary region aplasia and cleft lip and palate. Congenital cardiac anomalies are common.
Antenatal diagnosis
Antenatal diagnosis is possible by ultrasonographic monitoring.
Genetic counseling
The condition seems to be inherited as an autosomal recessive trait.
Prognosis
Prognosis is poor.

                            Last update:
                            January 2010


Holoprosencephaly-radial heart renal anomalies syndrome

A rare multiple congenital anomalies syndrome characterised by holoprosencephaly, predominantly radial limb deficiency (absent thumbs, phocomelia), heart defects, kidney malformations and absence of gallbladder. Variable manifestations include vertebral anomalies, cleft lip/palate, microphthalmia, absent nose, dysplastic ears, hearing loss, colobomas of the iris and retina and/or bifid uvula.


A rare complex brain malformation characterized by incomplete cleavage of the prosencephalon, and affecting both the forebrain and face and resulting in neurological manifestations and facial anomalies of variable severity.

Summary:
Epidemiology
Prevalence is estimated to be 1/10,000 live and still births and 1/250 conceptuses, with worldwide distribution.
Clinical description
Three classical forms of holoprosencephaly (HPE) of increasing severity are described based on the degree of anatomical separation: lobar, semi-lobar and alobar HPE. Milder subtypes include midline interhemispheric variant and septopreoptic HPE. There is, however, a continuous spectrum of abnormal separation of the hemispheres that extends from aprosencephaly/atelencephaly, the most severe end of the spectrum, to microform HPE, a less severe midline defect without the typical HPE brain characteristics. There is significant inter- and intrafamilial clinical variability across this spectrum. In most cases, there is a correlation between the severity of the facial anomalies and the brain defect (except in cases of mutation in the ZIC2 gene). In decreasing severity, the main craniofacial features are cyclopia, proboscis, premaxillary agenesis, median or bilateral cleft lip/palate, coloboma, retinal dysplasia, choanal stenosis, pyriform sinus stenosis, hypotelorism, solitary maxillary median incisor (SMMI) or even normal face. Severe forms are often fatal and mortality is correlated with the severity of brain malformation and associated defects. In surviving children, a wide range of associated manifestations are reported: developmental delay, hydrocephalus, motor impairment, spasticity, feeding difficulties and oromotor dysfunction, epilepsy, hypothalamic dysfunction. Endocrine disorders due to pituitary defects such as central diabetes insipidus are frequent.
Etiology
HPE is due to incomplete cleavage of the prosencephalon between the 18th and 28th day of gestation. The etiology is typically genetic and often oligogenic; however, environmental factors during this period (maternal diabetes or hypocholesterolemia during gestation) may contribute. HPE may also be associated with certain syndromes or chromosomal abnormalities (such as Smith-Lemli-Opitz syndrome, Hartsfield Syndrome and trisomy 13). In isolated HPE, at least 20 genes have been implicated: major genes include SHH (7q36), ZIC2  (13q32), SIX3 (2p21), GLI2 (2q14), FGF8 (10q24) and FGFR1 (8p11) in addition to more than 15 minor genes. The major common effect of the identified pathogenic mutations is the impairment of SHH activity leading to disruption of the ventral midline of the brain, and interference with the early stages of forebrain and eye development. SHH-dosage is crucial in the disease mechanism and might determine disease severity.
Diagnostic methods
Most severe cases are detected by systematic ultrasound scan and magnetic resonance imaging (MRI) during pregnancy or after birth. At the other end of the spectrum, diagnosis is based on clinical features.
Differential diagnosis
Differential diagnosis includes anencephaly, severe congenital hydrocephalus, Walker-Warburg syndrome, large interhemispheric cyst, otocephaly and other midline defects, as well as syndromic and chromosomal-related forms.
Antenatal diagnosis
Due to the high clinical and genetic variability, prenatal diagnosis is based on ultrasound scans and MRI rather than on molecular diagnosis, and may be useful in mothers with diabetes and those with a family history of HPE. Some parents of a child with a structural unbalanced chromosome rearrangement (e.g., deletion, duplication) have a balanced chromosome rearrangement and should be offered chromosome analysis by chorionic villus biopsy or amniocentesis.
Genetic counseling
Genetic counseling (GC) is strongly recommended for affected families; it is particularly complex and requires thorough clinical evaluation and family history, with close attention to possible risk factors (especially maternal diabetes), microform findings in relatives, and associated signs. If a genetic etiology is established in a proband, specific counseling for recurrence risk is indicated. In non-syndromic HPE, all modes of inheritance have been described; however, most cases are complex with digenic or oligogenic inheritance.
Management and treatment
Treatment is symptomatic and supportive, and requires a multidisciplinary approach.
Prognosis
Prognosis depends on severity and the associated complications.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Christèle DUBOURG  - Dr Alinoë LAVILLAUREIX  - Pr Sylvie ODENT | ITHACA*

                                * European Reference Network


A genetic syndrome with limb reduction defects characterized by skeletal abnormalities of the upper limbs and mild-to-severe congenital cardiac defects.

Summary:
Epidemiology
Holt-Oram syndrome (HOS) prevalence is estimated at 1/ 100,000 live births (in Hungary), but various cases have been published worldwide.
Clinical description
The clinical picture of HOS covers a wide spectrum of upper extremity defects, always including the radial ray, and cardiac defects. Radial ray upper limb anomalies include carpal bone malformation(s) as well as triphalangeal or absent thumb(s), phocomelia, hypoplasia or aplasia involving the radius often resulting in unequal arm lengths, transverse upper limb defects including abnormal forearm pronation and supination. Patients may have more severe left than right upper-limb abnormalities. Most frequent congenital cardiac malformations observed are atrial septal defect, ostium secundum type (ASD) and ventricular septal defect (VSD). Conduction abnormalities like paroxysmal atrial fibrillation, sometimes associated with various degrees of atrioventricular block, have been reported. Other variable anomalies reported include craniofacial, axillary, tracheal, vertebral and lower-limb anomalies, as well as deafness, abdominal situs inversus and renal abnormalities, but in many cases these findings reflect phenocopy syndromes rather than HOS itself.
Etiology
HOS is caused by a mutation in the TBX5 gene located on the long arm of chromosome 12 (12q24.1). The TBX5 gene encodes T-box5, a transcription factor regulating the expression of other genes in developing heart and limbs. More than 85% of the clinically diagnosed HOS individuals carry a TBX5 mutation.
Diagnostic methods
Diagnosis of HOS is based on clinical findings and family history. It can be confirmed by molecular genetic analyses.
Differential diagnosis
Differential diagnosis includes heart-hand syndrome type 2, heart-hand syndrome type 3, brachydactyly-long thumb, SAL4-related disorders (Okihiro and acro-renal-ocular syndrome), ulnar-mammary syndrome, Slovenian type heart-hand syndrome, Fanconi anemia, distal 22q11.2 microdeletion syndrome, VACTERL association, thalidomide embryopathy, fetal valproate syndrome.
Antenatal diagnosis
Prenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known HOS mutation. In women with HOS, cardiac defects should be evaluated by a cardiologist to determine what monitoring and care may be needed during pregnancy.
Genetic counseling
The majority of the HOS mutations occur de novo. HOS is inherited in an autosomal dominant manner with complete penetrance for upper-limb malformations, and 75% penetrance for congenital heart malformations and with variable expressivity leading to a wide spectrum of phenotypes. Genetic counseling should be offered to parents with a TBX5 mutation informing them of their 50% risk of transmitting it on to their children. Molecular genetic testing is not sufficient to precisely predict the severity of upper-limb and congenital heart anomalies.
Management and treatment
Management is multidisciplinary and includes geneticists, cardiologists, orthopedic surgeons and pediatric orthopedics as well as social support networks. Patients with advanced heart block may require a permanent pacemaker. An echocardiogram is recommended every one to five years if cardiac defects are present. Electrocardiograms (EKGs) are recommended annually for adults.
Prognosis
Prognosis is variable. Functional impact in everyday life is based on the type and severity of upper-limb anomalies. Life expectancy depends on the severity of cardiac anomalies.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Dr Craig BASSON


Holzgreve syndrome is an extremely rare, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by renal agenesis with Potter sequence, cleft lip/palate, oral synechiae, cardiac defects, and skeletal abnormalities including postaxial polydactyly. Intestinal nonfixation and intrauterine growth restriction are also associated. There have been no further descriptions in the literature since 1988.