Autosomal recessive generalized dystrophic epidermolysis bullosa, intermediate form

A rare dystrophic epidermolysis bullosa (DEB) characterized by generalized cutaneous and mucosal blistering that is not associated with severe deformities.

Summary:
Epidemiology
Its exact prevalence is unknown but this sub-type represents the second most common recessive DEB (RDEB), the first one being severe RDEB. The prevalence of all RDEB sub-types, with the exclusion of severe RDEB, has been estimated at 1/2,000,000 in the United States.
Clinical description
Under the term intermediate RDEB are grouped a spectrum of phenotypes, showing highly variable severity of the cutaneous and mucosal involvement. The disease manifests at birth or during the neonatal period with generalized blistering. Aplasia cutis congenita (congenital absence of the skin) can also be observed at birth. Healing of blisters results in the development of milia, atrophic scarring (less severe than in severe RDEB), dystrophic nails, and, occasionally, albopapuloid lesions (ivory-white colored, scar-like papules) and scalp abnormalities. In some patients, the scarring phenomena can lead to a certain degree of pseudosyndactyly and loss of nail plates. Extracutaneous involvement is similar but less severe than in severe RDEB with no hand/foot deformities associated with this disease. Oral cavity lesions and excessive dental caries are common. Patients have a lower risk of esophageal strictures and corneal injury than severe RDEB. Growth delay and anemia are rare. Genitourinary tract involvement is rare. The risk of developing squamous cell carcinomas (SCC) is also increased but less common than in severe RDEB and occurs later in adulthood.
Etiology
The disease is caused by mutations within the type VII collagen gene (COL7A1; 3p21.31) that lead to an alteration of function or a reduction in the amounts of collagen VII. This impairs collagen VII assembly into anchoring fibrils, which anchor the basement membrane to the underlying dermis. This in turn causes reduced skin resistance to minor trauma.
Diagnostic methods
Diagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples. Genetic testing confirms the diagnosis.
Differential diagnosis
The differential diagnosis includes other forms of EB. In the neonatal period, aplasia cutis congenita, herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, bullous impetigo, and staphylococcal scalded skin syndrome may need to be considered.
Antenatal diagnosis
Antenatal diagnosis can be recommended in families with this RDEB subtype, depending on the individual degree of severity.
Genetic counseling
The pattern of inheritance 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 at each pregnancy.
Management and treatment
Management is preventive: protective padding of the skin reduces blistering and careful wound care prevents secondary infection and reduces scarring. Oral hygiene is important for management of caries. Nutritional requirements should be evaluated by a dietitian. Esophageal strictures are treated by balloon dilatation with fluoroscopic guidance. A regular follow-up is necessary for the surveillance of SCC. The treatment of SCC is surgical and involves full-thickness excision with wide margins.
Prognosis
In most cases, life expectancy is normal. However, there is an increased risk of development of metastasizing squamous cell carcinomas with a cumulative risk of mortality of 21.5% by age 55.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Carmen SALAVASTRU | ERN-Skin*

                                * European Reference Network


Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form

A severe form of dystrophic epidermolysis bullosa (DEB) characterized by generalized cutaneous and mucosal blistering and scarring associated with severe deformities and major extracutaneous involvement.

Summary:
Epidemiology
The reported prevalence at birth varies between populations, from to 1/333,000 in the United States to 1/77,000 in Europe.
Clinical description
Blisters develop spontaneously or after the mildest trauma at birth or during the neonatal period and affect all of the body (with predilection for skin over bony prominences) with extensive involvement of the oral and gastrointestinal mucosa. Congenital skin ulceration with extensive denudation of a body area may be present. Lesions heal with retracting scars and milia. Epidermolysis bullosa (EB) nevi may occur. Excessive scarring can lead to adhesion of fingers and toes resulting to pseudosyndactyly, and to joint contractures that further cause disabling hand and foot deformities (''mitten deformities''). Scarring alopecia of the scalp and permanent loss of nail plates are also observed. Eye involvement is frequent and includes blepharitis, loss of eyelashes, ectropion, symblepharon, and corneal blisters that can lead to loss of vision. Chewing and swallowing difficulties are due to ankyloglossia, obliteration of the oral vestibules and progressive microstomia. Dental caries are numerous. Esophageal stricture is frequent and results in severe dysphagia. Anal and perianal erosions cause major pain during defecation and foster constipation. Extensive gastrointestinal involvement in combination with a hypercatabolic state due to permanent wounding, infection and inflammation, induce a state of chronic malnutrition which contributes to growth retardation, delayed puberty, osteopenia and osteoporosis. Urethral strictures may occur. Refractory anemia, iron deficiency and hypoalbuminemia are also observed. Nearly all patients develop at least one aggressive squamous cell carcinoma (SCC), typically during the third-fourth decade of life.
Etiology
The disease is caused by homozygous or compound heterozygous biallelic nonsense mutations in COL7A1 (3p21.31) that usually result in premature termination codons leading to a lack of functional collagen VII, the main constituent of anchoring fibrils that anchor the basement membrane to the dermis.
Diagnostic methods
Diagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples showing a cleavage plane located below the lamina densa of the cutaneous basement membrane zone. Genetic testing confirms the diagnosis.
Differential diagnosis
The differential diagnosis includes other forms of EB. In the neonatal period also herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, and staphylococcal scalded skin syndrome may need to be considered.
Antenatal diagnosis
Antenatal diagnosis is always recommended to parents having a child with severe RDEB. The disease-causing pathogenic variants should be disclosed before.
Genetic counseling
The pattern of inheritance 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 at each pregnancy.
Management and treatment
Protective padding of the skin reduces the blistering and careful wound care helps in preventing secondary infections. Treatment of pain and itch is highly warranted but partly limited in effectiveness. Regular follow-up at an EB-experienced dentist is recommended. Physiotherapy and occupational therapy are necessary to delay gradual loss of mobility and autonomy. Hand and foot deformities can be treated by surgery. Follow-up by a dietitian is essential and gastrostomy feeding may be necessary. Esophageal strictures are treated by balloon dilatation with fluoroscopic guidance. Transfusions, iron supplementation, and erythropoietin administration improve anemia and iron deficiency. Vitamin D supplementation may be indicated to prevent osteoporosis. Regular follow-up is necessary for the surveillance of SCC. Psychological support should be offered.
Prognosis
Life expectancy is significantly reduced, mostly due to the development of aggressive SCC with frequent metastases. By the age of 55, the cumulative risk for developing SCC and death is greater than 90% and about 80%, respectively. Other complications that affect prognosis include chronic renal failure, and more rarely, multifactorial cardiomyopathy.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Martin LAIMER | ERN-Skin*

                                * European Reference Network


Autosomal recessive generalized epidermolysis bullosa simplex

A rare, inherited, epidermolysis bullosa simplex characterized by neonatal onset of generalized or, less frequently, localized acral blistering. Milia are rare but atrophic scarring and dystrophic nails usually occur, along with focal keratoderma (palms and soles). Severe generalized blistering may cause perinatal death or persist during the entire life. Extracutaneous involvement is common, including anemia, growth retardation, oral cavity abnormalities (blisters and erosions, and caries) and constipation.


Autosomal recessive hyperinsulinism due to Kir6.2 deficiency

A rare, congenital, isolated hyperinsulinism disorder characterized by neonatal presentation of severe refractory hypoglycemia in the first two days of life, with limited response to medical management, sometimes requiring pancreatic resection. Newborns are often large for gestational age with mild to moderate hepatomegaly and diffuse form of hyperinsulinism due to Kir6.2 deficiency. Persistent hypoglycemia, hyperglycemia and type1 diabetes mellitus may develop later in life. Life-threatening hypoglycemic coma or status epilepticus have also been associated.


Autosomal recessive hyperinsulinism due to SUR1 deficiency

A rare, congenital, isolated hyperinsulinism disorder characterized by neonatal presentation of severe refractory hypoglycemia in the first two days of life, with limited response to medical management, sometimes requiring pancreatic resection. Newborns are often large for gestational age with mild to moderate hepatomegaly and diffuse form of hyperinsulinism due to SUR1 deficiency. Persistent hypoglycemia, hyperglycemia and type1 diabetes mellitus may develop later in life. Life-threatening hypoglycemic coma or status epilepticus have also been associated.


Autosomal recessive hypophosphatemic rickets

A rare, autosomal recessive renal phosphate-wasting disorder characterized by childhood-onset hypophosphatemia that clinically manifests with rickets and/or osteomalacia, slow growth/short stature, bone pain and skeletal deformities. Additional findings may include fatigue, muscle weakness and repeated bone fractures.


Autosomal recessive infantile hypercalcemia

A rare, genetic, phosphocalcic metabolism disorder characterized by early-onset hypercalcemia, hypophosphatemia, hypercalciuria, decreased intact parathyroid hormone serum levels and medullary nephrocalcinosis, typically manifesting with failure to thrive, hypotonia, vomiting, constipation and/or polyuria.


Autosomal recessive intermediate Charcot-Marie-Tooth disease type A

A subtype of autosomal recessive intermediate Charcot-Marie-Tooth (CMT) disease characterized by severe, early childhood-onset CMT neuropathy with prominent pes equinovarus deformity and impairment of hand muscles. Nerve conduction velocities usually range between 25-35 m/s and both axonal and demyelinating changes are observed on peripheral nerve pathology.


Autosomal recessive intermediate Charcot-Marie-Tooth disease type B

A rare subtype of autosomal recessive intermediate Charcot-Marie-Tooth (CMT) disease characterized by a CMT neuropathy associated with developmental delay, self-abusive behavior, dysmorphic features and vestibular Schwannoma. Motor nerve conduction velocities demonstrate features of both demyelinating and axonal pathology.


Autosomal recessive intermediate Charcot-Marie-Tooth disease type C

A rare subtype of autosomal recessive intermediate Charcot-Marie-Tooth (CMT) disease characterized by childhood to adulthood-onset of progressive, moderate to severe, predominantly distal, mostly lower limb muscle weakness and atrophy, foot deformities (including pes cavus and hammer toes), absent deep tendon reflexes and distal sensory loss associated with decreased motor and sensory nerve conduction velocities and features of both demyelinating and axonal neuropathy on sural nerve biopsy.


Autosomal recessive intermediate Charcot-Marie-Tooth disease type D is a rare hereditary motor and sensory neuropathy characterized by childhood onset of unsteady gait, pes cavus, frequent falls and foot dorsiflexor weakness slowly progressing to distal upper and lower limb muscle weakness and atrophy, distal sensory impairment and reduced tendon reflexes. Additional symptoms may include bilateral sensorineural hearing impairment and neuropathic pain.


Autosomal recessive isolated optic atrophy

A rare hereditary optic atrophy characterized by an early onset of bilateral optic nerve degeneration without other systemic features. Clinical manifestations include pallor of the optic disks, severe but slowly progressing visual impairment, and in some patients also paracentral scotoma, photophobia and dyschromatopsia.


Autosomal recessive Kenny-Caffey syndrome

A rare, primary bone dysplasia characterized by prenatal and postnatal growth retardation, short stature, cortical thickening and medullary stenosis of the long bones, absent diploic space in the skull bones, hypocalcemia due to the hypoparathyroidism, small hands and feet, delayed mental and motor development, intellectual disability, dental anomalies, and dysmorphic features, including prominent forehead, small deep-set eyes, beaked nose, and micrognathia.


Autosomal recessive lethal neonatal axonal sensorimotor polyneuropathy

A rare, genetic, autosomal recessive axonal hereditary motor and sensory neuropathy disease characterized by prenatal onset of a severe sensorimotor axonal polyneuropathy (reflected by reduced fetal movement and polyhydramnios), manifesting, at birth, with respiratory failure requiring mechanical ventilation, profound muscular hypotonia, rapidly progressing distal muscle weakness, and absent deep tendon reflexes, in the absence of contractures, leading to death before 8 months of age. Neuropathological findings show severe loss of large- and medium-sized myelinated fibers without signs of demyelination.


Autosomal recessive leukoencephalopathy-ischemic stroke-retinitis pigmentosa syndrome

A rare neurologic disease characterized by global developmental delay, intellectual disability, multiple ischemic lesions in brain MRI, behavioral abnormalities, dystonia, choreic movements and pyramidal syndrome, facial dysmorphism (hypertelorism, arched palate, macroglossia), retinitis pigmentosa, scoliosis, seizures.


Autosomal recessive lower motor neuron disease with childhood onset

A rare, genetic, neuromuscular disease characterized by proximal muscle weakness with an early involvement of foot and hand muscles following normal motor development in early childhood, a rapidly progressive disease course leading to generalized areflexic tetraplegia with contractures, severe scoliosis, hyperlordosis, and progressive respiratory insufficiency leading to assisted ventilation. Cranial nerve functions are normal and tongue wasting and fasciculations are absent. Milder phenotype with a moderate generalized weakness and slower disease progress was reported.


Autosomal recessive malignant osteopetrosis

A rare congenital disorder of bone resorption characterized by generalized skeletal densification.

Summary:
Epidemiology
Osteopetrosis is very rare. The incidence is estimated at 1/250 000 live births. The disease is more frequent in specific geographic regions and ethnic groups where consanguinity is common.
Clinical description
Bone marrow failure, fractures and visual impairment are the classical features of the disease, which begins in early infancy or in fetal life. It results from the failure of osteoclasts to resorb immature bone. This leads to abnormal bone marrow cavity formation and to the clinical signs and symptoms of bone marrow failure. It is accompanied by hepatosplenomegaly due to compensatory extramedullary hematopoiesis. Impaired bone remodeling causes bony narrowing of the cranial nerve foramina, which results in cranial nerve (especially optic nerve) compression. Pathologically, there is a persistence of the primary spongiosa characterized by cores of calcified cartilage within bone. Abnormal remodeling of primary, woven bone to lamellar bone results in 'brittle' bone that is prone to fracture. A rare form of the disease is associated with severe central nervous system dysfunction.
Etiology
The disease is genetically heterogeneous and caused by biallelic mutations. Over 50% of cases are due to mutations in the TCIRG1 gene and another 15% are due to mutations in the CLCN7 gene. A small number of patients with 'pure' recessive osteopetrosis have been described with mutations in OSTM1, and SNX10 gene, whereas mutations in TNFSF11 (RANKL) or TNFRSF11A (RANK) were found in some of the 'osteoclast-poor' forms.
Diagnostic methods
The clinical and radiological features establish the diagnosis. The genetic tests can be performed to confirm the diagnosis and to distinguish the exact form of the disease. Among imaging studies conventional radiography alone can show all the main radiological patterns of osteopetrosis, above all the abnormal increased bone density. Computed Tomography (CT) offers a higher level of detail and a higher spatial resolution than conventional radiography (helpful in a better detection of small associated fractures). MRI of the brain should be performed to assess the presence of cranial nerves involvement, hydrocephalus, and vascular abnormalities. Dual-Energy-X-rays-absorptiometry (DXA) can be used to quantify the increase in bone mass density, even if this tool is unable to predict the fracture risk in patients with osteopetrosis.
Differential diagnosis
Infantile onset osteopetrosis should be distinguished from the much milder autosomal dominant adult disease, the intermediated recessive form of osteopetrosis, and the carbonic anhydrase II deficiency syndrome, which is associated with renal tubular acidosis and less severe osteopetrosis. In doubtful cases a bone biopsy may help in excluding other differential diagnoses.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variants have previously been identified in both parents.
Genetic counseling
Genetic analysis is important to recognize classical and atypical forms, being also essential for treatment strategy. Transmission is autosomal recessive. Genetic counseling should be offered to affected individuals, as well as to at-risk couples (both subjects are carriers of a disease-causing mutation) which have a 25% risk of having an affected child at each pregnancy.
Management and treatment
Patients may require blood transfusions, treatment for infections and management of their developmental and visual problems. Bone marrow transplant can alleviate many features of the disease but needs to be performed early to minimize optic nerve encroachment. Hematopoietic stem cell transplantation is contraindicated in presence of mutations in OSTM1 or TNFSF11 (RANKL) gene.
Prognosis
The prognosis is variable but improves if bone marrow transplant is performed early.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Dr Elena PEDRINI | ERN BOND* - Dr Paolo SPINNATO

                                * European Reference Network


Autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency

A group of genetic variants of mendelian susceptibility to mycobacterial diseases (MSMD) comprised of MSMD due to complete interferon gamma receptor 1 (IFN-gammaR1) deficiency, complete IFN-gammaR2 deficiency, complete interleukin-12 subunit beta (IL12B) deficiency, complete interleukin-12 receptor subunit beta-1 (IL-12RB1) deficiency and complete ISG15 deficiency.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
This group of diseases has extreme clinical variability ranging from relatively mild infections with bacillus Calmette-Guérin (BCG) and salmonellosis (in IL12B and IL-12RB1 deficiencies) to severe and often fatal infections with BCG and other environmental mycobacteria (complete IFN-gammaR1 and IFN-gammaR2 deficiencies).
Etiology
Autosomal recessive MSMD due to a complete deficiency is caused by mutations in one of 5 genes: IFNGR1, IFNGR2, IL12B , IL12RB1 and ISG15. Mutations in these genes impair IL-12 dependent IFN-gamma immunity.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Autosomal recessive mendelian susceptibility to mycobacterial diseases due to a partial deficiency

A group of genetic variants of mendelian susceptibility to mycobacterial diseases (MSMD) due to autosomal recessive mutations in the IFNGR1 and IFNGR2 genes which lead to a residual response of IFN-gamma.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Infections in those with autosomal recessive MSMD due to a partial deficiency usually occur after the age of 3 to adulthood. Partial IFN-gammaR1 deficient patients experience infections that are more commonly due to localized non-tuberculosis mycobacterial (NTM) infections. They are also vulnerable to Mycobacterium tuberculosis. Infections in those with a partial IFN-gammaR2 deficiency are due to Mycobacterium bovis BCG and Mycobacterium abscessus. Manifestations include fever, weight loss, lymphadenopathy and hepatosplenomegaly. The infections are usually mild and, with treatment, patients remain in relatively good health.
Etiology
Autosomal recessive MSMD due to a partial deficiency is caused by mutations in either the IFNGR1 or IFNGR2 genes. These mutations lead to patients that have only a residual response to IFN-gamma and consequently have selective susceptibility to BCG and non-tuberculosis environmental mycobacteria (EM) infections and in rare cases to tuberculosis infections.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency

A rare primary immunodeficiency characterized by increased susceptibility to infections with candida albicans and weakly pathogenic mycobacteria, such as mycobacterium bovis. Patients present in infancy with chronic mucocutaneous candidiasis of varying severity, disseminated mycobacterial disease, absence of palpable axillary and cervical lymph nodes, reduced thymus size, and variable hepatosplenomegaly. The immunological phenotype comprises mild T-cell lymphopenia, absence of type 1 natural killer T-cells and mucosal-associated invariant T-cells, and low levels of type 3 innate lymphoid cells.


Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency

A genetic variant of mendelian susceptibility to mycobacterial diseases (MSMD) characterized by a partial deficiency in IFN-gammaR1, leading to a residual response to IFN-gamma and, consequently, to recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).

Summary:
Epidemiology
The prevalence is unknown. The same homozygous mutations have been reported in 14 patients in 11 kindreds from Poland, Portugal, Spain and Chile, thus reflecting a founder effect.
Clinical description
Patients present with moderately severe mycobacterial infections, BCG or EM diseases. These infections are recurrent but less severe than those seen in MSMD due to complete IFN-gammaR1 and IFN-gammaR2 deficiencies (see these terms). Infections with Mycobacterium tuberculosis have also been reported in patients with this disorder.
Etiology
Autosomal recessive MSMD due to partial IFN-gammaR1 deficiency is caused by homozygous mutations in the IFNGR1 gene on chromosome 6q23-q24 that encodes the IFN-gamma receptor ligand binding chain. The most common mutation is, by far, I87T. This mutation leads to the expression of IFN-gamma receptors on the cell surface with no signal transduction capacity and they therefore only show a partial response to IFN-gamma.
Diagnostic methods
Diagnosis is made by laboratory analysis. Low production of IL12p40 is detected in blood after BCG and BCG+IFN-gamma activation. Cells of patients show a residual response to IFN-gamma in terms of Stat-1 DNA-binding (GAS-binding activity) and HLA-II induction. A mutational analysis will identify a mutation in the IFNGR1 gene. Low levels of IFN-gamma were detected in the serum of the patients.
Differential diagnosis
Other genetic etiologies of MSMD should be excluded.
Antenatal diagnosis
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible.
Management and treatment
BCG vaccinations should be avoided in those with a known mutation in IFNGR1. Patients should be treated with antibiotics and, if necessary, with recombinant IFN-gamma.
Prognosis
Prognosis is usually good.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency

Autosomal recessive mendelian susceptibility to mycobacterial diseases (MSMD) due to partial IFNgammaR2 deficiency is a genetic variant of MSMD (see this term) characterized by a partial deficiency in IFN-gammaR2, leading to a residual response to IFN-gamma and consequently to recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).

Summary:
Epidemiology
The prevalence is unknown. Only one patient has been reported with this variant to date.
Clinical description
The patient presented with a mild infection caused by BCG and M. abscessus.
Etiology
Autosomal recessive MSMD due to partial IFNgammaR2 deficiency is caused by a homozygous mutation (R114C) in IFNGR2 on chromosome 21q22.1-22.2 that encodes the IFN-gamma receptor ligand binding chain. This mutation leads to a residual cellular response to IFN-gamma in terms of IL12p40 production.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial JAK1 deficiency

A rare primary immunodeficiency characterized by recurrent atypical mycobacterial infections, accompanied by relatively minor viral infections, on an immunological background of reduced induction of expression of interferon-regulated genes and dysregulated cytokine production, as revealed by laboratory studies. Global developmental delay and occurrence of non-hematopoietic malignancy at a young age have been reported in association.


Autosomal recessive multiple pterygium syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital pterygia (webbing) mainly affecting the neck and large joints, arthrogryposis multiplex, short stature, and craniofacial dysmorphism (including ptosis, downslanting palpebral fissures, high-arched palate, and retrognathia). Additional manifestations are decreased movements, facial weakness, respiratory distress, vertebral anomalies, scoliosis, anomalies of the fingers, and cryptorchidism, among others. The disease is a non-lethal variant of multiple pterygium syndrome.


Autosomal recessive myogenic arthrogryposis multiplex congenita is a rare inherited neuromuscular disease characterized by prenatal presentation (usually in the second trimester) of reduced fetal movements and abnormal positioning resulting in joint abnormalities that may involve both lower and upper extremities and is usually symmetric, severe hypotonia at birth with bilateral club foot, motor development delay, mild facial weakness without opthalmoplegia, absent deep tendon reflexes, normal motor and sensory nerve conduction velocities, no cerebellar or pyramidal involvement, and progressive disease course with loss of ambulation after the first decade of life.


A rare, isolated nail anomaly characterized by claw-shaped, thick, hyperplastic, hard and hyperpigmented nails, subungual hyperkeratosis, onycholysis and slow nail growth. Variable degree of disease severity has been reported.


Autosomal recessive optic atrophy, OPA7 type

A rare, syndromic, hereditary optic neuropathy disorder characterized by early-onset, severe, progressive visual impairment, optic disc pallor and central scotoma, variably associated with dyschromatopsia, auditory neuropathy (e.g. mild progressive sensorineural hearing loss), sensorimotor axonal neuropathy and, occasionally, moderate hypertrophic cardiomyopathy.


Autosomal recessive palmoplantar keratoderma and congenital alopecia

Autosomal recessive palmoplantar hyperkeratosis and congenital alopecia (PPK-CA) is a rare genetic skin disorder characterized by congenital alopecia and palmoplantar hyperkeratosis. It is usually associated with cataracts, progressive sclerodactyly and pseudo-ainhum.

Summary:
Epidemiology
To date, autosomal recessive PPK-CA has been reported in two families (seven affected individuals). An additional sporadic patient was likely affected by the same condition.
Clinical description
Similarly to the dominant variant, autosomal recessive PPK-CA usually presents during infancy. Its very early onset is often characterized by fading of facial, scalp and body hair within the first months of life without subsequent re-growth. Body and facial keratosis pilaris are additional features which appear in the following years. Skin thickening of palms and soles develops during infancy and may have an unusual pattern affecting the two sides of fingers and palms, but usually sparing the palmar surfaces. Periungueal involvement is typical and leads to secondary nail dystrophy. Autosomal recessive PPK-CA shows a relatively more severe evolution compared to the dominant variant as many patients develop sclerodactyly, small joint contractures and pseudo-ainhum. The original family also had congenital cataract.
Etiology
The genetic basis of autosomal recessive PPK-CA is unknown.
Differential diagnosis
Palmoplantar keratoderma and congenital alopecia/hypotrichosis is also found in ectodermal dysplasias and keratinization disorders, including hydrotic ectodermal dysplasia; hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma yndrome; KID syndrome; odonto-onycho-dermal dysplasia; Lelis syndrome; mutilating palmoplantar keratoderma with periorificial keratotic plaques; and Schöpf-Schulz-Passarge syndrome.
Genetic counseling
Transmission appears to be autosomal recessive.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Dr Marco CASTORI


Autosomal recessive polycystic kidney disease

A rare, genetic hepatorenal fibrocystic syndrome characterized by cystic dilatation and ectasia of renal collecting tubules, and a ductal plate malformation of the liver resulting in congenital hepatic fibrosis. Clinical presentation, whilst typically in utero or at birth, is variable and in the most severe cases includes Potter-sequence, oligohydramnios, pulmonary hypoplasia, and massively enlarged echogenic kidneys.

Summary:
Epidemiology
Prevalence is estimated at 1/20,000 live births. Male and female children are equally affected.
Clinical description
The clinical spectrum is broad and may include variable degrees of renal insufficiency, mild to severe life-threating neonatal respiratory distress/failure due to pulmonary hypoplasia, hyponatremia, hypertension and predisposition to urinary tract infections. Patients can progress to end-stage renal disease (ESRD) at varying ages. Congenital hepatic fibrosis (CHF) is invariably presents at birth, although may be clinically undetectable. The progressive manifestations of CHF typically include portal hypertension (pHTN), gastrointestinal varices and associated bleeding, bile duct disease (Caroli syndrome and cholangitis) and hepatosplenomegaly.
Etiology
PKHD1 (6p12.2-3) is the most frequently identified causative gene, and encodes the ciliary protein fibrocystin. Mutations in a cilia-related gene, DZIP1L (3q22.3), encoding a zinc finger protein, has also been identified.
Diagnostic methods
The hepatorenal phenotype and a family history consistent with autosomal-recessive inheritance is suggestive of the disease. Ultrasound typically shows hyperechogenic and enlarged kidneys, with retained contour and microcysts. Liver sonography shows biliary duct ectasia, a heterogeneous liver and possibly signs of pHTN and associated varices. Liver function tests typically remain in the normal ranges but thrombocytopenia and splenomegaly may be signs of pHTN. Genetic testing can confirm the causative mutation.
Differential diagnosis
Main differential diagnoses are other hereditary cystic kidney diseases including autosomal dominant polycystic kidney disease, HNF1beta-associated cystic nephropathies, cystic kidney dysplasia and nephronophthisis, as well as rare metabolic diseases such as glutaric aciduria type II.
Antenatal diagnosis
Suspicious prenatal ultrasound findings include bilaterally hyperechogenic, enlarged kidneys with poor cortico-medullary differentiation, with or without oligohydramnios and cysts. Prenatal genetic testing is possible where a mutation has been previously identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive. The risk of recurrence in siblings of an affected child is 25%.
Management and treatment
Treatment is supportive with conservative management of chronic kidney disease and hepatic symptoms. In newborns, pulmonary hypoplasia may require mechanical or high frequency ventilation. Hypertension needs aggressive management, often requiring a combination of several drugs, among which angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) are the mainstays. Peritoneal dialysis is recommended as first choice renal replacement treatment (RRT) for children with end-stage renal disease (ESRD). Renal transplantation is the best solution in case of ESRD. Depending on the hepatic phenotype, combined liver and kidney transplantation may be necessary. Regular monitoring of the liver disease is required to identify complications. Liver transplantation may be necessary. Multidisciplinary support should be considered for associated neurocognitive and behavioral problems.
Prognosis
The disease is associated with reduced life expectancy, although survival is improving. In the case of neonatal respiratory distress, mortality has been described as high as 30-40%. For patients surviving the neonatal period, about 50% will develop ESRD within the first decade of life. CHF is an important cause of morbidity and mortality.

                            Last update:
                            March 2019

                            - Expert reviewer(s):
                            Dr Max Christoph LIEBAU | ERKNet*

                                * European Reference Network


Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity

A rare, genetic primary immunodeficiency characterized by recurrent respiratory and skin viral infections (Epstein-Barr virus, herpes simplex virus, human papillomavirus), deficient spontaneous cytotoxicity of natural killer cells, but preserved antibody-dependent cellular cytotoxicity. No other abnormalities are present on immunologic work-up.


Autosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.

Summary:
Epidemiology
Exact prevalence of non-syndromic microcephaly is not known. MCPH is more common in Asian and Middle Eastern populations than in Caucasians, in whom an annual incidence of 1/1,000,000 is reported. It is more common in specific populations, e.g. northern Pakistanis. Consanguinity appears to play a role in incidence.
Clinical description
Patients have a reduction in head circumference (HC) at birth of at least 2 standard deviations (SD) below ethnically matched, age- and sex-related mean values. Microcephaly can be observed by week 32 of pregnancy. Subsequent head growth is very slow, and HC worsens during infancy: below -3SD before 6 months, and usually between -4SD and -12SD in adults. Mild to moderate non-progressive intellectual impairment is found, in the absence of any significant neurological deficit. Seizures may be present (10%). Delay in early motor milestones and speech delay are common. Most patients have hyperactive behavior.
Etiology
Ten subtypes based on the 11 genes have been differentiated. However, patients are basically phenotypically indistinguishable. MCPH is caused by mutations in MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, STIL, CEP63, CEP135 , CASC5  and PHC1. These mutations appear to lead to reduced generation of cerebral cortical neurons during embryonic neurogenesis. Some patients do not harbor these mutations. Some carry mutations in one of the genes of Meier-Gorlin syndrome (see this term), i.e. CDC6, CDT1, ORC1, ORC4, ORC6.
Diagnostic methods
Diagnosis is generally based on clinical signs. Reduced occipitofrontal circumference along with mild to moderate cognitive impairment, in the absence of other malformations or dysmorphism, and with normal height to mildly shortened height, are the most common diagnostic criteria. MRI shows grossly normal, proportionately small-sized brain with some degree of gyral simplification, and small normal brainstem and cerebellum. Patients with mutations in WDR62 may show more severe cortical anomalies and may not fulfill the common criteria of MCPH. Molecular genetic testing is available for several genes. The condition can be diagnosed on prenatal ultrasound but absence of microcephaly does not exclude the diagnosis.
Differential diagnosis
MCPH and Seckel syndrome belong to a clinical continuum, as mutations of some genes (CENPJ, CEP152) result in either phenotype. The distinction between MCPH and Seckel relies on a historical distinction between microcephalic patients with normal stature and patients with reduced stature. Normal fundus examination is important to distinguish MCPH from the microcephaly-chorioretinopathy syndromes. MRI is crucial to distinguish MCPH from other disorders with congenital microcephaly, such as lissencephaly, Norman-Roberts type (see this term) or infectious embryofetopathies. Assessment of maternal serum phenylalaninemia is mandatory to exclude maternal phenylketonuria (see this term).
Antenatal diagnosis
Prenatal testing and carrier testing are available for families with known gene mutations. When no mutation is identified, fetal MRI could be advised, but normal findings do not exclude the diagnosis.
Genetic counseling
Inheritance is autosomal recessive. Exact genotype-phenotype correlations have not been established.
Management and treatment
There is no specific etiologic treatment. Physical and speech therapy may be beneficial. Seizures are usually stabilized with common anticonvulsants. Ritalin may reduce hyperactivity.
Prognosis
Vital prognosis depends on severity and related manifestations but is generally good.

                            Last update:
                            March 2013

                            - Expert reviewer(s):
                            Pr Alain VERLOES


Autosomal recessive progressive external ophthalmoplegia

A rare genetic, neuro-ophthalmological disease characterized by progressive weakness of the external eye muscles, resulting in bilateral ptosis and diffuse, symmetric ophthalmoparesis. Additional signs may include generalized skeletal muscle weakness, muscle atrophy, sensory axonal neuropathy, ataxia, cardiomyopathy, and psychiatric symptoms. It is usually more severe than autosomal dominant form.


Autosomal recessive proximal renal tubular acidosis

A rare autosomal recessive form of proximal renal tubular acidosis characterized by an isolated defect in the proximal tubule leading to the decreased reabsorption of bicarbonate and consequentially to urinary bicarbonate wastage. Presentation is typically with hyperchloremic acidosis, usually occurring in childhood. Extrarenal manifestations include ocular abnormalities (band keratopathy, glaucoma, and cataracts), intellectual disability and severe growth retardation. Other features like dental enamel defects, basal ganglia calcification and pancreatitis are sometimes present.


Autosomal recessive Robinow syndrome (RRS) is the less common type of Robinow syndrome (RS, see this term) characterized by short-limb dwarfism, costovertebral segmentation defects and abnormalities of the head, face and external genitalia.

Summary:
Epidemiology
Fewer than 100 cases of this type have been reported in the literature to date.
Clinical description
The disorder is usually recognizable at birth or in early childhood. The clinical signs are generally far more severe in recessive cases of RS than in the dominant form, particularly skeletal abnormalities. All patients with the recessive form of RS suffer from vertebral segmentation abnormalities, resulting in scoliosis and chest deformities. Rib fusions are considered to be characteristic of the autosomal recessive form.
Etiology
The syndrome is caused by mutations in the ROR2 gene (9q22).
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Juliana MAZZEU


Autosomal recessive secondary polycythemia not associated with VHL gene

A rare, hereditary, hematologic disease characterized by an increase in hemoglobin, hematocrit and erythrocyte mass resulting in plethora or ruddy complexion, headache, dizziness, tinnitus and exertional dyspnea. In some cases, thrombophlebitis and arthralgia have also been reported.


Autosomal recessive severe congenital neutropenia due to CSF3R deficiency

A rare, genetic, primary immunodeficiency disorder characterized by predisposition to recurrent, life-threatening bacterial infections associated with decreased peripheral neutrophil granulocytes (absolute neutrophil count less than 500 cells/microliter), resulting from recessively inherited loss-of-function mutations in the CSF3R gene. Full maturation of all three lineages in the bone marrow and refractoriness to in vivo rhG-CSF treatment are associated.


Autosomal recessive severe congenital neutropenia due to CXCR2 deficiency

A rare, genetic, primary immunodeficiency disorder characterized by recurrent bacterial infections (including septic thrombophlebitis and subacute bacterial endocarditis) and neutropenia without lymphopenia or warts, resulting from recessively inherited mutations in CXCR2.


Autosomal recessive sideroblastic anemia

Congenital autosomal recessive sideroblastic anemia (ARSA) is a non-syndromic, microcytic/hypochromic sideroblastic anemia, present from early infancy and characterized by severe microcytic anemia, which is not pyridoxine responsive, and increased serum ferritin.

Summary:
Epidemiology
To date, fewer than 30 unrelated genetically characterized individuals with congenital ARSA have been reported in the northern hemisphere.
Clinical description
Congenital ARSA presents in early infancy, within the first weeks or months after birth, and is associated with severe microcytic anemia, increased transferrin saturation and increased serum ferritin. Clinical features are those of anemia and iron overload and include pallor, fatigue, weakness, breathlessness, splenomegaly, hyperglycemia, glucose intolerance and skin hyperpigmentation. Complications of iron overload include heart arrhythmias, heart attacks and liver disease (cirrhosis, cancer). Patients need blood transfusions to survive and do not respond to treatment with pyridoxine (vitamin B6).
Etiology
ARSA is caused by a homozygous or compound heterozygous mutation in the SLC25A38 gene located on chromosome 3p22.1.
Diagnostic methods
Diagnosis is based on clinical findings together with full blood examination including blood smear and reticulocyte count, measurement of iron stores and bone marrow aspirate showing ringed sideroblasts. Unresponsiveness to pyridoxine treatment often leads to confirming SLC25A38 gene mutation analysis.
Differential diagnosis
Differential diagnosis includes other types of sideroblastic anemia and particularly bears resemblance with X-linked sideroblastic anemia (XLSA, see this term).
Antenatal diagnosis
In case of family history, prenatal diagnosis by amniocentesis or chorionic villus sampling and cytogenetic analysis is possible, as early diagnosis in a child may be of great benefit for treatment of anemia and avoidance of iron overload, historically the main cause of early death.
Genetic counseling
The SLC25A38 gene mutation is transmitted as an autosomal recessive trait. Genetic counseling should be offered to affected individuals and their families informing them of the possibilities of carrier testing for at-risk family members and the genetic risk for transmitting it on to their children.
Management and treatment
ARSA differs from X-linked sideroblastic anemias because it is usually more severe and is not responsive to treatment with pyridoxine. Treatment is supportive and involves hematological monitoring, the surveillance of iron levels and nearly always comprises chronic blood transfusions. If iron overload has already developed, iron chelation can be used to normalize iron levels. In some cases, bone marrow transplantation is considered as a successful treatment option.
Prognosis
Prognosis is variable and depends on the severity of microcytic anemia. Quality of life is affected in the case chronic blood transfusions are needed. In well treated patients life expectancy is thought to be normal.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Pr Clara CAMASCHELLA


Autosomal recessive spastic ataxia of Charlevoix-Saguenay

A rare neurodegenerative disorder characterized by early-onset cerebellar ataxia, a pyramidal syndrome and peripheral neuropathy.

Summary:
Epidemiology
It was initially described in the Charlevoix-Saguenay region of Quebec where incidence of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) at birth has been estimated at 1 in 1,932. The incidence and prevalence worldwide remain unknown but ARSACS is now considered one of the more common recessive ataxias worldwide with cases described in several countries including Turkey, Japan, the Netherlands, Italy, Belgium, France, Spain and more than 20 other countries.
Clinical description
ARSACS is a slowly progressive disease with variable clinical presentation. The age of onset in non-Quebec patients is variable (ranging from late infantile, juvenile to early-adult onset) but in individuals from Quebec, onset occurs between 12 and 18 months of age with gait disturbance and walking difficulties. Other early signs of cerebellar ataxia include upper limbs incoordination, dysarthria and nystagmus. The pyramidal syndrome is characterized by lower limbs spasticity, brisk patellar tendon reflexes and the Babinski sign. Onset of the peripheral neuropathy generally occurs later and leads to absence of the Achilles tendon reflex, distal amyotrophy, pes cavus and deep sensory disturbances (impaired vibration sense). Retinal hypermyelination (without vision loss) is a constant feature in ARSACS patients from Quebec but may be absent in patients from other countries. Cognitive impairments related to cerebellar involvement have been documented. Other manifestations may include spasms, lower limb neuropathic pain and bladder dysfunction.
Etiology
ARSACS is caused by autosomal recessive mutations in the SACS gene (13q11), which encodes a large protein of partially known function named sacsin.
Diagnostic methods
The diagnosis of ARSACS is established by molecular genetic testing. Clinical diagnosis relies on the results of neurophysiological data (signs of both axonal and demyelinating neuropathy, with nerve conduction studies revealing loss of sensory nerve conduction and reduced motor conduction velocities). MRI brain revealed superior cerebellar vermian atrophy and T2 linear ''striped'' hypointensities in pons. Retinal examination may also be useful for diagnosis.
Differential diagnosis
Differential diagnoses include other autosomal recessive ataxias, such as Friedreich ataxia, ataxia with vitamin E deficiency (AVED), Abetalipoproteinemia and hereditary forms of spastic paraplegia, in particular spastic paraplegia type 7, spastic paraplegia type 30 and spastic paraplegia type 20 (SPG20-Troyer syndrome).
Antenatal diagnosis
Antenatal diagnosis is possible for at-risk couples (both individuals are carriers of a disease-causing mutation) by genetic testing.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is symptomatic aiming towards improving motor control, decreasing spasticity and should include a rehabilitation team approach that includes physiotherapy, occupational therapy and pharmacotherapy.
Prognosis
Most patients become wheelchair-dependent by the fifth decade of life. Death generally occurs during the sixth decade but survival into the seventies has been reported.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Pr Bernard BRAIS  - Pr Cynthia GAGNON  - Dr Jean MATHIEU


Autosomal recessive spastic ataxia with leukoencephalopathy

A rare, genetic, autosomal recessive spastic ataxia disease characterized by cerebellar ataxia, spasticity, cerebellar (and in some cases cerebral) atrophy, dystonia, and leukoencephalopathy.


Autosomal recessive spastic ataxia-optic atrophy-dysarthria syndrome

A rare, genetic, autosomal recessive spastic ataxia disease characterized by onset in early childhood of spastic paraparesis, cerebellar ataxia, dysarthria and optic atrophy.


Autosomal recessive spastic paraplegia type 11

A complex hereditary spastic paraplegia characterized by progressive lower limbs weakness and spasticity, upper limbs weakness, dysarthria, hypomimia, sphincter disturbances, peripheral neuropathy, learning difficulties, cognitive impairment and dementia. Magnetic resonance imaging shows thin corpus callosum, cerebral atrophy, and periventricular white matter changes.


Autosomal recessive spastic paraplegia type 14 is a rare, complex hereditary spastic paraplegia characterized by adulthood-onset of slowly progressive spastic paraplegia of lower limbs presenting with spastic gait, hyperreflexia, and mild lower limb hypertonicity associated with mild intellectual disability, visual agnosia, short and long-term memory deficiency and mild distal motor neuropathy. Bilateral pes cavus and extensor plantar responses are also associated.


Autosomal recessive spastic paraplegia type 15 is a complex form of hereditary spastic paraplegia characterized by a childhood to adulthood onset of slowly progressive lower limb spasticity (resulting in gait disturbance, extensor plantar responses and decreased vibration sense) associated with mild intellectual disability, mild cerebellar ataxia, peripheral neuropathy (with distal upper limb amyotrophy) and retinal degeneration. Thin corpus callosum is a common imaging finding.


Autosomal recessive spastic paraplegia type 20 (SPG20) is a type of complex hereditary spastic paraplegia characterized by an onset in infancy of progressive spastic paraparesis associated with distal amyotrophy, psuedobulbar palsy, motor and cognitive delays, mild cerebellar signs (dysarthria, dysdiadochokinesia, mild intention tremor), short stature and subtle skeletal abnormalities (pes cavus, mild talipes equinovarus, kyphoscoliosis). SPG20 is due to mutations in the SPG20 gene (13q13.1), which encodes the protein spartin.


Autosomal recessive spastic paraplegia type 21 is a complex type of hereditary spastic paraplegia characterized by an onset in adolescence or adulthood of slowly progressive spastic paraparesis associated with the additional manifestations of apraxia, cognitive and speech decline (leading to dementia and akinetic mutism in some cases), personality disturbances and extrapyramidal (e.g. oromandibular dyskinesia, rigidity) and cerebellar (i.e. dysdiadochokinesia and incoordination) signs. Subtle abnormalities (e.g. developmental delays) may be noted earlier in childhood. A thin corpus callosum and white matter abnormalities are equally reported on magnetic resonance imaging.


Autosomal recessive spastic paraplegia type 23 (SPG23) is a rare, complex type of hereditary spastic paraplegia that presents in childhood with progressive spastic paraplegia, associated with peripheral neuropathy, skin pigment abnormalities (i.e. vitiligo, hyperpigmentation, diffuse lentigines), premature graying of hair, and characteristic facies (i.e. thin with ''sharp'' features). The SPG23 phenotype has been mapped to a locus on chromosome 1q24-q32.


Autosomal recessive spastic paraplegia type 24

A very rare, pure form of spastic paraplegia characterized by an onset in infancy of lower limb spasticity associated with gait disturbances, scissor gait, tiptoe walking, clonus and increased deep tendon reflexes. Mild upper limb involvement may occasionally also be associated.


Autosomal recessive spastic paraplegia type 25 (SPG25) is a rare, complex type of hereditary spastic paraplegia characterized by adult-onset spastic paraplegia associated with spinal pain that radiates to the upper or lower limbs and is related to disk herniation (with minor spondylosis), as well as mild sensorimotor neuropathy. The SPG25 phenotype has been mapped to a locus on chromosome 6q23-q24.1.


Autosomal recessive spastic paraplegia type 26 (SPG26) is a rare, complex type of hereditary spastic paraplegia characterized by the onset in childhood/adolescence (ages 2-19) of progressive spastic paraplegia associated mainly with mild to moderate cognitive impairment and developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy. Less commonly reported manifestations include skeletal abnormalities (i.e. pes cavus, scoliosis), dyskinesia, dystonia, cataracts, cerebellar signs (i.e. saccadic dysfunction, nystagmus, dysmetria), bladder disturbances, and behavioral problems. SPG26 is caused by mutations in the B4GALNT1 gene (12q13.3), encoding Beta-1, 4 N-acetylgalactosaminyltransferase 1.


Autosomal recessive spastic paraplegia type 27 is a rare, pure or complex hereditary spastic paraplegia characterized by a variable onset of slowly progressive lower limb spasticity, hyperreflexia and extensor plantar responses, that may be associated with sensorimotor polyneuropathy, decreased vibration sense, lower limb distal muscle wasting, dysarthria and mild to moderate intellectual disability.


Autosomal recessive spastic paraplegia type 28 is a pure form of hereditary spastic paraplegia characterized by a childhood or adolescent onset of slowly progressive, pure crural muscle spastic paraparesis which manifests with mild lower limb weakness, gait difficulties, extensor plantar responses, and hyperreflexia of lower extremities. Less common manifestations include cerebellar oculomotor disturbance with saccadic eye pursuit, pes cavus and scoliosis. Some patients also present pin and vibration sensory loss in distal legs.


Autosomal recessive spastic paraplegia type 32 (SPG32) is a rare, complex type of hereditary spastic paraplegia characterized by a slowly progressive spastic paraplegia (with walking difficulties appearing at onset at 6-7 years of age) associated with mild intellectual disability. Brain imaging reveals thin corpus callosum, cortical and cerebellar atrophy, and pontine dysraphia. The SPG32 phenotype has been mapped to a locus on chromosome 14q12-q21.


Autosomal recessive spastic paraplegia type 35 is a rare form of hereditary spastic paraplegia characterized by childhood (exceptionally adolescent) onset of a complex phenotype presenting with lower limb (followed by upper limb) spasticity with hyperreflexia and extensor plantar responses, with additional manifestations including progressive dysarthria, dystonia, mild cognitive decline, extrapyramidal features, optic atrophy and seizures. White matter abnormalities and brain iron accumulation have also been observed on brain magnetic resonance imaging.


Autosomal recessive spastic paraplegia type 39

A rare autosomal recessive complex spastic paraplegia characterized by upper motor neuron involvement and peripheral neuropathy with an onset between childhood and early adulthood. Patients present with progressive spasticity, hyperreflexia, and distal upper and lower muscle wasting. Reduced cognitive functioning and cerebellar ataxia have also been reported. MR imaging may reveal cerebellar and/or spinal cord atrophy.


Autosomal recessive spastic paraplegia type 43 is a rare, complex hereditary spastic paraplegia characterized by a childhood to adolescent onset of progressive lower limb spasticity, associated with mild to severe gait disturbances, extensor plantar responses, muscle weakness and severe distal atrophy, frequently with upper limb involvement. Additional features may include joint contractures, distal sensory loss and brisk or absent deep tendon reflexes. Other signs, such as depression, memory loss, optic atrophy (with vision loss) and brain iron deposition (revealed by brain imagery), have also been reported.


Autosomal recessive spastic paraplegia type 44 (SPG44) is a very rare, complex form of hereditary spastic paraplegia characterized by a late-onset, slowly progressive spastic paraplegia associated with mild ataxia and dysarthria, upper extremity involvement (i.e. loss of finger dexterity, dysmetria), and mild cognitive impairment, without the presence of nystagmus. A hypomyelinating leukodystrophy and thin corpus callosum is observed in all cases and psychomotor development is normal or near normal. SPG44 is caused by mutations in the GJC2 gene (1q41-q42) encoding the gap junction gamma-2 protein.


Autosomal recessive spastic paraplegia type 45 is a rare, pure or complex form of hereditary spastic paraplegia characterized by onset in infancy of progressive lower limb spasticity, abnormal gait, increased deep tendon reflexes and extensor plantar responses, that may be associated with intellectual disability. Additional signs, such as contractures in the lower limbs, amyotrophy, clubfoot and optic atrophy, have also been reported.


Autosomal recessive spastic paraplegia type 46 (SPG46) is a rare, complex type of hereditary spastic paraplegia characterized by an onset, in infancy or childhood, of the typical signs of spastic paraplegia (i.e. spastic gait and weakness of the lower limbs) associated with a variety of additional manifestations including upper limb spasticity and weakness, pseudobulbar dysarthria, bladder dysfunction, cerebellar ataxia, cataracts, and cognitive impairment that can progress to dementia. Brain imaging may show thinning of the corpus callosum and mild atrophy of the cerebrum and cerebellum. SPG46 is due to mutations in the GBA2 gene (9p13.2) encoding non-lysosomal glucosylceramidase.


Autosomal recessive spastic paraplegia type 48

A rare, pure or complex form of hereditary spastic paraplegia usually characterized by a pure phenotype of a slowly progressive spastic paraplegia associated with urinary incontinence with an onset in mid- to late-adulthood. A complex phenotype, with the additional findings of cognitive impairment, sensorimotor polyneuropathy, ataxia, parkinsonism, and dystonia as well as thin corpus callosum and white matter lesions (seen on brain and spine magnetic resonance imaging), has also been reported.


Autosomal recessive spastic paraplegia type 53 (SPG53) is a very rare, complex type of hereditary spastic paraplegia characterized by early-onset spastic paraplegia (with spasticity in the lower extremities that progresses to the upper extremities) associated with developmental and motor delay, mild to moderate cognitive and speech delay, skeletal dysmorphism (e.g. kyphosis and pectus), hypertrichosis and mildly impaired vibration sense. SPG53 is due to mutations in the VPS37A gene (8p22) encoding vacuolar protein sorting-associated protein 37A.


Autosomal recessive spastic paraplegia type 54 (SPG54) is a rare, complex form of hereditary spastic paraplegia characterized by the onset in early childhood of progressive spastic paraplegia associated with cerebellar signs, short stature, delayed psychomotor development, intellectual disability and, less commonly, foot contractures, dysarthria, dysphagia, strabismus and optic hypoplasia. SPG54 is caused by mutations in the DDHD2 gene (8p11.23) encoding phospholipase DDHD2.


Autosomal recessive spastic paraplegia type 55 (SPG 55) is a rare, complex type of hereditary spastic paraplegia characterized by childhood onset of progressive spastic paraplegia associated with optic atrophy (with reduced visual acuity and central scotoma), ophthalmoplegia, reduced upper-extremity strength and dexterity, muscular atrophy in the lower extremities, and sensorimotor neuropathy. SPG55 is caused by mutations in the C12ORF65 gene (12q24.31) encoding probable peptide chain release factor C12orf65, mitochondrial.


Autosomal recessive spastic paraplegia type 56

A rare form of hereditary spastic paraplegia characterized by delayed walking, toe walking, unsteady and spastic gait, hyperreflexia of the lower limbs, and extensor plantar responses. Upper limbs spasticity and dystonia, subclinical axonal neuropathy, cognitive impairment and intellectual disability have also been associated.


Autosomal recessive spastic paraplegia type 57 (SPG57) is an extremely rare, complex type of hereditary spastic paraplegia, characterized by onset in infancy of pronounced leg spasticity (leading to the inability to walk independently), reduced visual acuity due to optic atrophy, and distal wasting of the hands and feet due to an axonal demyelinating sensorimotor neuropathy. SPG57 is caused by mutations in the TFG  gene (3q12.2) encoding protein TFG, which is thought to play a role in ER microtubular architecture and function.


Autosomal recessive spastic paraplegia type 59

A rare, complex hereditary spastic paraplegia characterized by an early onset of progressive lower limb spasticity, tip-toe walking, scissor gait, hyperreflexia and clonus that may be associated with borderline intellectual disability. Nystagmus and pes equinovarus have also been reported.


Autosomal recessive spastic paraplegia type 5A is a form of hereditary spastic paraplegia characterized by either a pure phenotype of slowly progressive spastic paraplegia of the lower extremities with bladder dysfunction and pes cavus or a complex presentation with additional manifestations including cerebellar signs, nystagmus, distal or generalized muscle atrophy and cognitive impairment. Age of onset is highly variable, ranging from early childhood to adulthood. White matter hyperintensity and cerebellar and spinal cord atrophy may be noted, on brain magnetic resonance imaging, in some patients.


Autosomal recessive spastic paraplegia type 60 is a rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, inability to walk, hypertonia and impaired vibration sense at ankles, with complicating signs including sensory impairment, nystagmus, motor axonal neuropathy and mild intellectual disability.


Autosomal recessive spastic paraplegia type 61 (SPG61) is a rare, complex form of hereditary spastic paraplegia characterized by an onset in infancy of spastic paraplegia (presenting with the inability to walk unsupported and a scissors gait) associated with a motor and sensory polyneuropathy with loss of terminal digits and acropathy. SPG61 is due to a mutation in the ARL6IP1 gene (16p12-p11.2) encoding the ADP-ribosylation factor-like protein 6-interacting protein 1.


Autosomal recessive spastic paraplegia type 62

A pure or complex form of hereditary spastic paraplegia characterized by an onset in the first decade of life of spastic paraperesis (more prominent in lower than upper extremities) and unsteady gait, as well as increased deep tendon reflexes, amyotrophy, cerebellar ataxia, and flexion contractures of the knees, in some.


Autosomal recessive spastic paraplegia type 63 (SPG63) is an extremely rare and complex form of hereditary spastic paraplegia characterized by an onset in infancy of spastic paraplegia (presenting with delayed walking and a scissors gait) associated with short stature, and normal cognition. Periventricular deep white matter changes in the corpus callosum are noted on brain imaging. SPG63 is caused by a homozygous mutation in the AMPD2 gene (1p13.3) encoding AMP deaminase 2.


Autosomal recessive spastic paraplegia type 64 is an extremely rare and complex form of hereditary spastic paraplegia (see this term), reported in only 4 patients from 2 families to date, characterized by spastic paraplegia (presenting between the ages of 1 to 4 years with abnormal gait) associated with microcephaly, amyotrophy, cerebellar signs (e.g. dysarthria) aggressiveness, delayed puberty and mild to moderate intellectual disability. SPG64 is due to mutations in the ENTPD1 gene (10q24.1), encoding ectonucleoside triphosphate diphosphohydrolase 1.


Autosomal recessive spastic paraplegia type 66

A rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, severe gait disturbances leading to a non-ambulatory state, absent deep tendon reflexes and amyotrophy. Additional signs include severe sensorimotor neuropathy, pes equinovarus and mild intellectual disability. Cerebellar and corpus callosum hypoplasia, as well as colpocephaly, are observed on neuroimaging.


Autosomal recessive spastic paraplegia type 67 is an extremely rare, complex hereditary spastic paraplegia characterized by an infancy or childhood onset of global developmental delay and progressive spasticity with tremor in the distal limbs, increased deep tendon reflexes and extensor plantar responses, which may be associated with mild intellectual disability. Additional features include muscle wasting and cerebellar abnormalities.


Autosomal recessive spastic paraplegia type 69

A rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, global developmental delay, hyperreflexia, clonus and extensor plantar reflexes, associated with dysarthria, intellectual disability, cataracts and hearing impairment.


Autosomal recessive spastic paraplegia type 70 is a very rare, complex subtype of hereditary spastic paraplegia that presents in infancy with delayed motor development (i.e. crawling, walking) and is characterized by lower limb spasticity, increased deep tendon reflexes, extensor plantar responses, impaired vibratory sensation at ankles, amyotrophy and borderline intellectual disability. Additional signs may include gait disturbances, Achilles tendon contractures, scoliosis and cerebellar abnormalities.


Autosomal recessive spastic paraplegia type 71

A type of autosomal recessive pure hereditary spastic paraplegia characterized by infancy onset of crural spastic paraperesis with scissors gait, extensor plantar response, and increased tendon reflexes. Neuroimaging reveals a thin corpus callosum and electromyography and nerve conduction velocity studies are normal.


Autosomal recessive spastic paraplegia type 74 is a rare, genetic, spastic paraplegia-optic atrophy-neuropathy-related (SPOAN-like) disorder characterized by childhood onset of mild to moderate spastic paraparesis which manifests with gait impairment that very slowly progresses into late adulthood, hyperactive patellar reflex and bilateral extensor plantar response, in association with optic atrophy and typical symptoms of peripheral neuropathy, including reduced or absent ankle reflexes, lower limb atrophy and distal sensory impairment. Reduced visual acuity and pes cavus are frequently reported.


Autosomal recessive spastic paraplegia type 75

A rare, complex hereditary spastic paraplegia characterized by an early onset and slow progression of spastic paraplegia associated with cerebellar signs, nystagmus, peripheral neuropathy, extensor plantar responses and borderline to mild intellectual disability. Additional features of hypo- or areflexia, mild upper limb involvement and significant visual impairment (optic atrophy, vision loss, astigmatism) have been reported.


Autosomal recessive spastic paraplegia type 76 is a rare, complex hereditary spastic paraplegia characterized by adult onset slowly progressive, mild to moderate lower limb spasticity and hyperreflexia, resulting in gait disturbances, commonly associated with upper limb hyperreflexia and dysarthria. Foot deformities (usually pes cavus) and extensor plantar responses are also frequent. Additional features may include ataxia, lower limb weakness/amyotrophy, abnormal bladder function, distal sensory loss and mild intellectual deterioration.


Autosomal recessive spastic paraplegia type 77 is a rare, pure or complex hereditary spastic paraplegia characterized by an infancy to childhood onset of slowly progressive lower limb spasticity, delayed motor milestones, gait disturbances, hyperreflexia and various muscle abnormalities, including weakness, hypotonia, intention tremor and amyotrophy. Ocular abnormalities (e.g. strabismus, ptosis) and other neurological abnormalities, such as dysarthria, seizures and extensor plantar responses, may also be associated.


Autosomal recessive spastic paraplegia type 78

A rare autosomal recessive complex spastic paraplegia characterized by mostly adult-onset progressive spasticity and weakness predominantly affecting the lower limbs, axonal motor and sensory neuropathy, and cerebellar symptoms like ataxia, dysarthria, and oculomotor abnormalities. Variable degrees of cognitive impairment may also be present. Subtle extrapyramidal involvement and supranuclear gaze palsy were reported in some cases. Features on brain imaging include cerebral and cerebellar atrophy and sometimes abnormalities of the corpus callosum or basal ganglia.


Autosomal recessive spastic paraplegia type 9B

A rare complex hereditary spastic paraplegia characterized by early onset of slowly progressive spastic para- or tetraparesis, increased tendon reflexes, positive Babinski sign, global developmental delay, cognitive impairment, and pseudobulbar palsy. Additional manifestations include dysmorphic facial features, tremor, short stature, and urinary incontinence.


Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome

A rare autosomal recessive syndromic cerebellar ataxia characterized by the association of early-onset cerebellar ataxia with hearing loss and blindness. Patients may also present demyelinating peripheral motor neuropathy. Cerebral MRI shows alterations of the cerebellar white matter without cerebellar atrophy.


A rare condition of variable severity associated with vertebral and rib segmentation defects and characterised by a short neck with limited mobility, winged scapulae, a short trunk, and short stature with multiple vertebral anomalies at all levels of the spine.

Summary:
Epidemiology
The incidence and prevalence are unknown. The disease seems to be more frequent in the Puerto Rican population.
Clinical description
Autosomal recessive spondylocostal dysostosis (ARSD) is usually diagnosed in the neonatal period. The main skeletal malformations include fusion of the vertebrae, hemivertebrae, and rib fusion with other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of these malformations and leads to a dwarf-like appearance. As the thorax is small, infants frequently have respiratory insufficiency and repeated respiratory infections. Anomalies of the central nervous system, genitourinary tract and heart (spina bifida, meningocele, renal and ureteral abnormalities, hypospadias, complex congenital heart disease, atrial septal defect, anomalous pulmonary venous return etc.) have been reported but are not common. Facial dysmorphism and intellectual deficit are occasional features.
Etiology
So far, four genes, all involved in the Notch signalling pathway - DLL3 (19q13.2), MESP2 (15q26.1), LFNG (7p22.3) and HES7 (17p13.1) - have been identified but mutations in these genes do not account for all of the cases.
Diagnostic methods
Diagnosis is clinical and may be supported by ultrasonography and spine radiographs.
Antenatal diagnosis
Prenatal diagnosis is possible using fetal ultrasound.
Genetic counseling
The disease is inherited as an autosomal recessive trait.
Management and treatment
Management includes intensive medical care, bone surgery, and orthopedic treatment.
Prognosis
ARSD may cause respiratory insufficiency that may lead to life-threatening complications in the first year of life.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Autosomal recessive spondylometaphyseal dysplasia, Mégarbané type

A rare, primary bone dysplasia characterized by intrauterine growth retardation, pre- and postnatal disproportionate short stature with short, rhizomelic limbs, facial dysmorphism, a short neck and small thorax. Hypotonia, cardiomegaly and global developmental delay have also been associated. Several radiographic findings have been reported, including ribs with cupped ends, platyspondyly, square iliac bones, horizontal and trident acetabula, hypoplastic ischia, and delayed epiphyseal ossification.


A rare type of Stickler syndrome characterized by moderate to severe sensorineural hearing loss, high myopia, retinal degeneration, vitreous anomalies, and epiphyseal dysplasia. Midface hypoplasia, cleft palate, as well as additional skeletal manifestations (such as platyspondyly, scoliosis, and tibial and femoral bowing at birth) have also been observed.


Autosomal semi-dominant severe lipodystrophic laminopathy

A rare familial partial lipodystrophy characterized by severe partial lipoatrophy affecting the limbs, trunk, and abdomen, together with faciocervical fat accumulation. Additional manifestations include diabetes, acanthosis nigricans, liver steatosis, and hypertriglyceridemia, as well as low serum leptin and adiponectin levels. Severe cardiac rhythm and conduction disturbances have also been reported.


Autosomal spastic paraplegia type 18 (SPG18) is a rare, complex type of hereditary spastic paraplegia characterized by progressive spastic paraplegia (presenting in early childhood) associated with delayed motor development, severe intellectual disability and joint contractures. A thin corpus callosum is equally noted on brain magnetic resonance imaging. SPG18 is caused by a mutation in the ERLIN2 gene (8p11.2) encoding the protein, Erlin-2.


A rare, pure or complex form of hereditary spastic paraplegia characterized by either a pure spastic paraplegia phenotype, usually presenting in the first or second decade of life, with spastic lower extremities, unsteady spastic gait, hyperreflexia and extensor plantar responses, or as a complicated phenotype with the additional manifestations of distal wasting, saccadic ocular movements, mild cerebellar ataxia and mild, distal, axonal neuropathy.


A rare, complex subtype of hereditary spastic paraplegia characterized by variable onset of slowly progressive lower limb spasticity and weakness and prominent cerebellar ataxia, associated with gait disturbances, dysarthria, increased deep tendon reflexes and extensor plantar responses. Additional features may include involuntary movements (i.e. clonus, tremor, fasciculations, chorea), decreased vibration sense, oculomotor abnormalities (e.g. nystagmus) and distal amyotrophy in the upper and lower limbs.


A rare autosomal dominant pure hereditary spastic paraplegia characterized by early childhood onset of slowly progressive crural spastic paraparesis presenting with spastic gait, mild stiffness at rest, hyperreflexia (in lower limbs), extensor plantar responses and, in some, mild postural tremor, pes cavus, sphincter disturbances and sensory loss at ankles.


A rare, genetic, multisystemic, chronic autoimmune disease characterized by the presence of systemic lupus erythematosus symptoms in two or more members of a single family. Patients present a wide spectrum of clinical manifestations, including cutaneous (malar rash, photosensitivity), ocular (keratoconjunctivitis sicca, retinopathy), gastrointestinal (oral ulceration, abdominal pain), cardiac (atherosclerosis, chest pain), pulmonary (serositis, pleurisy), musculoskeletal (arthralgia, myalgia), renal (nephritis, hematuria), obstetrical (increased spontaneous abortions, neonatal lupus), constitutional (fatigue, loss of appetite) and neuropsychiatric (mood and cognitive disorders) involvement, among others.


A rare, infectious disease characterized by variable severity and outcome, ranging from mild upper respiratory tract infection with fever and cough, to influenza-like illness with rapid progression to severe pneumonia, sepsis with shock, acute respiratory distress syndrome and even death. Additional manifestations may include conjunctivitis, nausea, abdominal pain, diarrhea, vomiting, multiple organ dysfunction, and encephalopathy.


A rare, congenital, ocular defect caused by anterior segment dysgenesis and characterized by anteriorly displaced Schwalbe's line and iris bands extending into the cornea. In contrast, Rieger's anomaly includes characteristic iris and pupil anomalies.


Axenfeld-Rieger syndrome (ARS) is a generic term used to designate overlapping genetic disorders, in which the major physical condition is anterior segment dysgenesis of the eye. Patients with ARS may also present with multiple variable congenital anomalies.

Summary:
Epidemiology
The syndrome has an estimated prevalence of 1/200,000.
Clinical description
The clinical manifestations of ARS are highly variable. Features can be divided into ocular and non-ocular findings. Ocular abnormalities mainly affect the iris: hypoplasia, corectopia or hole formation in the iris mimicking polycoria; cornea: prominent and anteriorly displaced Schwalbe's line (posterior embryotoxon); and the chamber angle: iris strands bridging the iridocorneal angle to the trabecular meshwork. Eye dysgenesis in ARS may cause increased ocular pressure (IOP) leading to glaucoma. Glaucoma can develop in infancy, but usually occurs in adolescence or early adulthood, occasionally after middle age. The most characteristic non-ocular findings are mild craniofacial dysmorphism, dental anomalies and redundant periumblical skin. Mid-face abnormalities include hypertelorism, telecanthus, maxillary hypoplasia with flattening of the mid-face, prominent forehead, and broad, flat nasal bridge. Dental abnormalities may include microdontia or hypodontia. Hypospadias in males, anal stenosis, pituitary abnormalities and growth retardation may also be observed.
Etiology
Patients with ARS have been found to have mutations in the transcription factor genes PITX2 (4q25) and FOXC1 (6p25). A large number of different mutations have been identified but there is no clear genotype-phenotype relationship. However, PITX2 mutations are mainly detected in ARS patients with non-ocular changes. The underlying genetic defect is unknown in 60% of cases, and at least two more loci have been associated with ARS.
Diagnostic methods
ARS is diagnosed by ophthalmologic and clinical examination. Associated systemic findings are supportive of diagnosis. Genetic testing can be used to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include iris hypoplasia (IH), primary congenital glaucoma (PCG) and Peters anomaly (see these terms). Absence of other corneal abnormalities, such as megalocornea, sclerocornea and corneal opacity are useful in distinguishing ARS from other anterior segment disorders.
Antenatal diagnosis
If the disease-causing mutation has been identified in a family, prenatal testing for at-risk pregnancies is possible.
Genetic counseling
The disorders that comprise the ARS spectrum are inherited in an autosomal dominant manner with high penetrance. Genetic counseling can be offered to patients and their families.
Management and treatment
An annual slit lamp examination should be performed, along with gonioscopy, IOP measurements and funduscopy to assess the retinal nerve fiber layer and optic nerve head involvement due to possible glaucoma. Autoperimetry (automated measurements of the visual fields) is necessary whenever glaucoma is suspected. Should glaucoma develop, drug therapy is recommended before surgery. In case of glaucoma, the goal of treatment is to reach low IOP. Surgery is performed if eye drops are not sufficient in lowering IOP. Medications that decrease aqueous output (beta-blockers, alpha-agonists and carbonic anhydrase inhibitors) are more beneficial than those affecting outflow. However, alpha-agonists should be used with caution in young children because of possible CNS depression. If surgery is necessary, the procedure of choice is trabeculectomy with the adjunctive use of antimetabolites. If photophobia is present in patients with corectopia and polycoria, contact lenses may be used to cover the holes in the iris.
Prognosis
Prognosis is good, particularly in the absence of glaucoma.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Dr Daniella BACH-HOLM  - Pr Zeynep TÜMER


Axial mesodermal dysplasia spectrum is a rare developmental defect during embryogenesis syndrome characterized by congenital manifestations of both oculo-auriculo-vertebral spectrum and caudal regression sequence. Phenotype is highly variable but patients typically present facial dysmorphism (incl. asymmetry, hypertelorism), auricular abnormalities (e.g. preauricular tags, microtia, absence of middle ear ossicles), skeletal malformations (hemivertebrae, hip dislocation, sacral agenesis/dysplasia, talipes equinovarus, flexion deformity of lower limbs), cardiac defects (dextrocardia, septal defects), renal and genitourinary anomalies (such as renal agensis/dysplasia, abnormal external genitalia, cryptorchidia), as well as anal anomalies such as anal atresia and rectovesical fistula.


Axial spondylometaphyseal dysplasia is a rare type of spondylometaphyseal dysplasia characterized by metaphyseal changes of the truncal-juxtatruncal bones associated with retinal dystrophy. Patients typically present progressive postnatal growth failure with rhizomelic shortening of the limbs, a deformed, hypoplastic thorax and retinitis pigmentosa or pigmentary retinal degeneration. Radiographic findings include short ribs with flared, cupped anterior ends, mild platyspondyly, lacy ilia and metaphyseal dysplasia of the proximal femora.


Axonal polyneuropathy associated with IgG/IgM/IgA monoclonal gammopathy

A rare acquired peripheral neuropathy characterized by symmetric, slowly progressive, predominantly sensory neuropathy, mostly limited to the legs with numbness and paresthesia of the distal leg and mild imbalance. Some patients may experience pain, weakness of foot dorsiflexion, mild proximal leg weakness, and/or upper limb involvement. The majority of patients have IgG monoclonal gammopathy. Systemic illnesses are absent in most cases.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital cataract, sensorineural hearing loss, developmental delay with variable degrees of intellectual disability, seizures, short stature, brachycephaly, and dysmorphic facial features (such as flat facial appearance, ptosis, short nasal tip, long philtrum, low-set and posteriorly rotated ears, and small mouth). Additional reported manifestations are skeletal abnormalities, nail dystrophy, mammary gland hypoplasia, and autism spectrum disorder.


Azygos continuation of the inferior vena cava

A rare vascular anomaly characterized by absence of the hepatic segment of the inferior vena cava and presence of an enlarged azygos vein (or in rare cases hemiazygos vein, if there is a left-sided inferior vena cava) draining the venous blood from the caudal segments. The post-hepatic segment of the inferior vena cava is present, draining only the hepatic veins into the right atrium. Most patients remain asymptomatic, if the anomaly is isolated. Association with congenital heart disease and asplenia or polysplenia syndromes has been reported.


B-cell chronic lymphocytic leukemia (B-CLL) is a type of B-cell non-Hodgkin lymphoma (see this term), and the most common form of leukemia in Western countries, affecting elderly adults (mean age of 67 and 72 years) with a slight male predominance (1.7:1), and characterized by a highly variable clinical presentation that can include asymptomatic disease or non-specific B-symptoms such as unintentional weight loss, severe fatigue, fever (without evidence of infection), and night sweats as well as cervical lymphadenopathy, splenomegaly and frequent infections. Some patients can also develop autoimmune complications such as autoimmune hemolytic anemia or immune thrombocytopenia (see these terms). The clinical course is extremely heterogeneous with survival ranging from a few months to several decades.


B-cell immunodeficiency-limb anomaly-urogenital malformation syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by almost complete lack of B-cells and severe hypogammaglobulinemia, anomalies of the hands and feet, urogenital malformations, and characteristic facial dysmorphism (including microcephaly, highly arched eyebrows, hypoplastic alae nasi, and micrognathia). Most patients are developmentally normal, although moderate mental retardation has also been described.


A rare mature B-cell neoplasm characterized by clonal proliferation of B-cell prolymphocytes, with prolymphocytes constituting more than 55% of lymphoid cells in peripheral blood. IG genes are clonally rearranged. Neoplastic cells are present in the bone marrow, peripheral blood, and spleen. Patients usually present with B symptoms, massive splenomegaly but absent or minimal lymphadenopathy, rapidly increasing lymphocyte count, anemia, and thrombocytopenia. Therapy response is poor.


B3GALT6-related spondylodysplastic Ehlers-Danlos syndrome

A form of spondylodysplastic Ehlers-Danlos syndrome due to variants in B3GALT6 and characterized by short stature, variable degrees of muscle hypotonia, joint hypermobility, especially of the hands, bowing of limbs and congenital or early onset, progressive kyphoscoliosis. Additional features include the typical craniofacial gestalt (prominent forehead, sparse hair, mid-face hypoplasia, blue sclerae, proptosis and abnormal dentition), hyperextensible, soft, thin, translucent and doughy skin, delayed motor and/or cognitive development, characteristic radiographic findings (spondyloepimetaphyseal dysplasia, platyspondyly, anterior beak of vertebral body, short ilia, elbow malalignment and generalized osteoporosis), joint contractures and ascending aortic aneurysm.

Summary:
Epidemiology
To date, 41 individuals with molecularly diagnosed B3GALT6-related spondylodysplastic EDS, have been reported.
Clinical description
The main features are short stature, variable degrees of muscle hypotonia, joint hypermobility, bowing of limbs and congenital or early onset, progressive kyphoscoliosis. Joint hypermobility, especially of the hands and feet, and soft, doughy and hyperextensible skin are some of the most striking characteristics. Facial dysmorphism includes prominent forehead, sparse hair, mid-face hypoplasia, blue sclerae, proptosis and abnormal dentition with discoloration of teeth. Most affected children present from infancy with delayed motor development and hypotonia; half of patients have delayed cognitive development. The majority of patients display severe kyphoscoliosis, which is usually congenital or early onset and progressive. Skeletal anomalies include platyspondyly, short iliac bones and elbow dislocation. Osteopenia has been frequently reported, usually in conjunction with fractures and luxations. Less frequent skeletal anomalies include cervical spine instability, pectus carinatum/excavatum, joint contractures, radioulnar synostosis, limited elbow extension, carpal synostosis, short metacarpals, ulnar deviation of fingers, oligodactyly, hip dysplasia, epiphyseal dysplasia of femoral heads, genu valgus, pes planus, talipes equinovarus, recurrent luxation of the toes and hallux valgus. Approximately one third of the patients have ophthalmological abnormalities, such as myopia, corneal opacity, sclerocornea, blue sclerae, microcornea, glaucoma, optic nerve atrophy and retinal detachment. Cardiovascular anomalies infrequently reported include mitral valve prolapse, aortic valve stenosis and aortic root aneurysm. Other less common features include urinary defects with nephroptosis, bilateral caliceal and ureteral dilatation, laryngeal cleft, tracheomalacia, spontaneous repeated pneumothoraces, chronic respiratory insufficiency, Wilms tumor, cryptorchidism, prominent superficial veins, hypoplastic nails. There are rare reports of sensorineural and conductive hearing loss and cleft palate.
Etiology
The disorder is due to variants of the B3GALT6 gene (1p36.33), encoding for galactosyltransferase II. This gene is responsible for the synthesis of the linker region of proteoglycans, which are essential components of the extracellular matrix of connective tissues.
Diagnostic methods
Diagnosis is based on clinical examination, radiological studies and molecular findings.
Differential diagnosis
Differential diagnosis includes spondyloepimetaphyseal dysplasias (e.g due to KIF22 or EXOC6B), the other forms of spondylodysplastyic EDSs, as well as other genetic syndromes characterized by kyphoscoliosis, joint hypermobility, skin hyperextensibility and short stature.
Antenatal diagnosis
Prenatal diagnosis is possible where a known pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management requires a multidisciplinary approach. Musculoskeletal anomalies, in particular kyphoscoliosis, may require a precocious orthopedic intervention. Specific regular follow-up is recommended based on the patient's clinical manifestation. Rehabilitation therapies must be tailored to the patient's characteristics.
Prognosis
Currently, data is limited with regard to life expectancy. Whilst four cases of death in infancy have been described, there are no known reasons to suspect reduced life expectancy. Functional consequences and quality of life depend on disease severity.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Stefano Giuseppe CARAFFI  - Dr Livia GARAVELLI | ITHACA*

                                * European Reference Network


B4GALT1-CDG is a congenital disorder of glycosylation characterised by macrocephaly due to Dandy-Walker malformation, hydrocephaly, hypotonia, myopathy and coagulation anomalies. To date, only one case has been reported. The syndrome is associated with mutations in the GALT1 gene (localised to region q13 of chromosome 9) leading to a deficiency in the Golgi apparatus enzyme beta-1,4-galactosyl transferase.


A form of spondylodysplastic Ehlers-Danlos syndrome due to variants in B4GALT7 and characterized by short stature, variable degrees of muscle hypotonia, joint hypermobility, especially of the hands, and bowing of limbs. Additional features include the typical craniofacial gestalt (mid-face hypoplasia, round, flat face, proptosis and narrow mouth), hyperextensible skin that is soft, thin, translucent and doughy, delayed motor and/or cognitive development, characteristic radiographic findings (such as radio-ulnar synostosis, radial head subluxation or dislocation, metaphyseal flaring and osteopenia) and ocular abnormalities.

Summary:
Epidemiology
To date, 34 individuals with molecularly diagnosed B4GALT7-related spondylodysplastic Ehlers-Danlos syndrome have been reported.
Clinical description
The main features in affected individuals are short stature, bowing of limbs, small joint hypermobility, hyperextensible, soft, doughy skin with delayed wound healing, and radioulnar synostosis. Facial dysmorphism includes short face with midface hypoplasia, proptosis, narrow mouth and loose skin also evident in the face. Most affected children present from infancy with delayed motor development and hypotonia; half of patients have delayed cognitive development. The most frequent skeletal anomalies are contractures or limited elbow movements, radioulnar synostosis, bowing of the ulna and radius, pes planus and osteopenia. Less frequently observed skeletal features include sagittal craniosynostosis, temporomandibular joint dislocation, scoliosis/kyphosis, vertebral coronal cleft, pectus carinatum, clavicular exostoses, patellar dislocation, hip dysplasia, bifid thumb, broad fingertips, ulnar deviation of fingers, equinovarus deformity and hallux valgus. Approximately half of the patients have ophthalmological abnormalities, such as hypermetropia, myopia, strabismus, blue sclerae, ptosis, nystagmus, glaucoma, megalocornea, iris and optic nerve coloboma, small optic nerves and cataracts. Dental anomalies include defective and discoloration of teeth. Less frequently reported features include cardiovascular anomalies (such as aortic/pulmonary stenosis and atrial septal defects) and urinogenetial defects (vesicoureteral reflux, cryptorchidism, hypogonadism, inguinal hernia) as well as hemidiaphragmatic eventration, varicose veins, lymphedema and multiple nevi. Sensorineural/conductive hearing loss and cleft palate are rarely reported.
Etiology
The disorder is due to variants of the B4GALT7 gene (5q35.3), encoding for galactosyltransferase I. This gene is responsible for the synthesis of the linker region of proteoglycans, essential components of the extracellular matrix in connective tissues.
Diagnostic methods
Diagnosis is based on clinical examination, radiological studies and molecular findings.
Differential diagnosis
Differential diagnosis includes other spondylodysplastic Ehlers-Danlos syndromes and genetic conditions with joint hypermobility, skin hyperextensibility and short stature.
Antenatal diagnosis
Prenatal diagnosis is possible where a known pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management requires a multi-disciplinary approach. Specific regular follow-up is recommended based on the patient's clinical manifestations. Rehabilitation therapy must be tailored to the patient's characteristics. Musculoskeletal anomalies may require a precocious orthopedic intervention.
Prognosis
Data is limited with respect to life expectancy; whilst there is only one adult patient reported in the literature, there are currently no known reasons suspect a reduced life expectancy. Functional consequences and quality of life depend on disease severity. The pathology is not progressive.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Gianluca CONTRO  - Dr Livia GARAVELLI | ITHACA*

                                * European Reference Network