Inverted duplicated chromosome 15 syndrome

A rare, complex chromosomal duplication/inversion in the region 15q11.2-q13.1 characterized by early central hypotonia, global developmental delay and intellectual deficit, autistic behavior, and seizures.

Summary:
Epidemiology
Prevalence at birth is estimated at 1 in 30,000 but may be an underestimate. In patients with developmental concerns (developmental delay, intellectual disability, or autism spectrum disorder) or multiple congenital anomalies, the prevalence of partial tetrasomy of chromosome 15 is estimated to range between 1/253-584. There is an observed male predilection of 2:1.
Clinical description
Presentation is typically with neonatal hypotonia, feeding difficulties and gross motor delay. Global developmental delay is typical in early childhood with speech and language particularly affected. Expressive language is absent or very poor and often echolalic. Comprehension is very limited and contextual. Intention to communicate is absent or very limited. Most children and adults have moderate to severe intellectual disability. The distinct behavioral disorder manifesting in children and adolescents has been widely described as autistic or autistic-like. Seizures occur in over half of affected individuals, with onset typically between 6 months and 9 years, and may include infantile spasms and myoclonic, tonic-clonic, tonic, atonic, atypical absences, and focal seizures. Various EEG (electroencephalography) abnormalities have been described. Muscle hypotonia is observed in almost all individuals, associated, in most cases, with joint hyperextensibility and drooling. Facial dysmorphism is absent or subtle, and major malformations are rare.
Etiology
Chromosome region 15q11q13, known for its instability, is highly susceptible to clinically relevant genomic rearrangements, such as supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15 (Inv dup(15)). It results in tetrasomy 15p and partial tetrasomy 15q. Large rearrangements, containing the Prader-Willi/Angelman syndrome critical region (PWS/ASCR), are responsible for the inv dup(15)/isodicentric 15 (idic(15)) phenotype.
Diagnostic methods
Diagnosis is established by standard cytogenetic and FISH (fluorescence in situ hybridization) analysis, using probes both from proximal chromosome 15 and from the PWS/ASCR. Microsatellite analysis on parental DNA or methylation analysis on the proband DNA are also needed to detect the parent-of-origin of the inv dup(15) chromosome. Array CGH (comparative genomic hybridization) has been shown to be a powerful approach for identifying and detecting both the increases in copy number of the 15q11.2q13.1 region and its extent, as well as atypical forms of idic(15).
Differential diagnosis
The possible occurrence of double supernumerary isodicentric chromosomes derived from chromosome 15, resulting in partial hexasomy of the maternally inherited PWS/ASCR, should be considered in the differential diagnosis. Mitochondrial encephalomyopathy, Rett and Angelman syndromes, and CDKL5 mutations should also be considered in the differential diagnosis.
Antenatal diagnosis
Due to possible maternal germline mosaicism, antenatal diagnosis maybe considered where there is an affected sibling.
Genetic counseling
Genetic counseling may be proposed due to possible maternal germline mosaicism but large rearrangements involving the PWS/ASCR and idic(15) are nearly always sporadic.
Management and treatment
Management of inv dup(15)/idic(15) includes a comprehensive neurophysiologic and developmental evaluation.
Prognosis
Life expectancy is not significantly reduced. Many adults have a severe intellectual disability with poor social interaction, and are unable to manage full self-care. Most live at home with their original family and a minority in a sheltered environment.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Agatino BATTAGLIA


IRF2BPL-related regressive neurodevelopmental disorder-dystonia-seizures syndrome

A rare genetic neurological disorder characterized by childhood onset of severe global neurodevelopmental regression with eventual loss of independent walking and loss of language and fine and gross motor skills, and development of severe dysphagia requiring tube feeding, seizures, cerebellar syndrome, dystonia, and other neurologic manifestations. Brain imaging shows progressive cerebral and/or cerebellar atrophy in most cases. A less severe phenotype associated with missense mutations shows no regression or movement abnormalities, ambulation is preserved, and brain imaging is normal.


IRIDA (Iron-refractory iron deficiency anemia) syndrome is a rare autosomal recessive iron metabolism disorder characterized by iron deficiency anemia (hypochromic, microcytic) that is often unresponsive to oral iron intake and partially responsive to parenteral iron treatment.

Summary:
Epidemiology
50 patients from 32 families of different ethnic origin have been described to date; however, it is likely that this condition is underdiagnosed.
Clinical description
Most IRIDA patients have no major clinical signs, except for pallor, and have normal growth and development. The degree of anemia is mostly mild and more pronounced during childhood. If anemia is severe, they may present with weakness, fatigue, dizziness and exercise-induced dyspnea. Laboratory tests show hypochromic, microcytic anemia with very low serum iron and transferrin saturation levels and normal/high serum hepcidin values. Serum ferritin levels are mostly within the normal range, or even slightly elevated after intravenous iron treatment.
Etiology
IRIDA syndrome is due to mutations the TMPRSS6 gene encoding Matriptase 2, a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis.
Diagnostic methods
Laboratory tests show hypochromic, microcytic anemia with very low serum iron and transferrin saturation levels and normal/high serum hepcidin values. Serum ferritin levels are mostly within the normal range, or even slightly elevated after intravenous iron treatment. Molecular testing confirms the diagnosis.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Dr Mayka SÁNCHEZ FERNÁNDEZ


Iridocorneal endothelial (ICE) syndrome describes a group of progressive corneal proliferative endotheliopathies comprised of Chandlers syndrome, Cogan-Reese syndrome and essential iris atrophy (see these terms), affecting mainly young adult females and characterized by iris holes and atrophy, papillary distortion, anterior synechiae, corneal edema and often with secondary glaucoma and corneal decompensation as complications


A rare retinal vasculopathy disease characterized by idiopathic retinal vasculitis (IRV), aneurysmal dilations (A) at arteriolar bifurcations, and neuroretinitis (N), which if untreated progresses to peripheral capillary non-perfusion, retinal neovascularization, and macular exudation, leading to severe, bilateral vision loss.


Isaac's syndrome is an immune-mediated peripheral motor neuron disorder characterized by continuous muscle fiber activity at rest resulting in muscle stiffness, cramps, myokymia, and pseudomyotonia.

Summary:
Epidemiology
Prevalence is unknown but 100 -200 cases have been reported so far.
Clinical description
The age of disease onset ranges from infancy to the sixth decade, with a peak incidence between forty and sixty. Isaac's syndrome is characterized by continuous muscle fiber activity at rest (even during sleep), resulting in cramps, muscle stiffness and weakness, pseudomyotonia, muscle twitching (visible myokymia), and fasciculation. Hyperhidrosis, muscle hypertrophy and hyporeflexia are also observed. Stiffness without severe pain is more remarkable in the distal than proximal muscles. In 20% of cases Isaac's syndrome is associated with malignancy (thymoma and small cell lung cancer) (see these terms). It is mainly associated with myasthenia gravis (see this term), but has incidentally been associated with other immune mediated diseases such as chronic inflammatory demyelinating polyneuropathy (CIDP), rheumatoid arthritis, Guillain-Barré syndrome, and systemic lupus erythematosus (see these terms). Some patients may present with a variant form known as Morvan syndrome (see this term) which is characterized by muscle activity and excessive perspiration and neurological findings with symptoms including personality changes, hallucinations, mood swings and sleeping disorders.
Etiology
The etiology for this disorder remains unknown. However, a role for the voltage-gated potassium channel complex (VGKC) in terminal nerve fibers has been implicated by the discovery of VGKC-complex antibodies. These antibodies are not against VGKC itself, but against Caspr2 and to a lesser extent in neuromyotonia against LGI1. These antibodies down-regulate VGKC leading to repeated action potentials. The precise meaning of increased levels of VGKC-complex antibodies without Caspr2 or LGI1 antibodies is currently controversial, as is the use of immunotherapy in this specific group.
Diagnostic methods
Diagnosis of Isaac's syndrome relies on history, physical findings, and electromyography (EMG). Typical findings are doublet, triplet or multiplet ('myokymic') motor unit discharges and fasciculations. 35-40% of patients have elevated levels of anti-VGKC-complex antibodies, which is more frequent in Morvan syndrome than in Isaac's syndrome.
Differential diagnosis
Differential diagnosis includes hereditary neuromyotonia or myokymia (with/without episodic ataxia) syndromes, cramp-fasciculation syndrome, motor neuron diseases (progressive spinal muscle atrophy, neuropathy, amyotrophic lateral sclerosis (ALS) (see this term), intoxication (gold, mercury, toluene, insecticides) and tetanus (see this term).
Management and treatment
Peripheral nerve hyperexcitability in Isaacs' syndrome can be treated with membrane-stabilizing drugs such as phenytoin, valproic acid, carbamazepine or lamotrigine, alone or in combination if necessary. If response is insufficient, oral corticosteroid (prednisolone) may be prescribed. The addition of non-steroid immunosuppressive drugs such as azathioprine and methotrexate may also be considered. Daily treatment with acetazolamide may improve twitching/writhing movements and eliminate episodes of loss of tone. Plasma exchange or intravenous immunoglobulin is indicated for severe neuromyotonia and for patients with Morvan's syndrome. In the paraneoplastic form, treatment of malignancy is warranted.
Prognosis
There is no cure for Isaac's syndrome although it is not fatal. Morvan's syndrome has a more severe course and can be fatal. The long-term prognosis for individuals with paraneoplastic Isaac's syndrome is dependent on the tumor course.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Dr M.J. [Maarten] TITULAER


Isobutyryl-CoA dehydrogenase deficiency is an inborn error of valine metabolism. The prevalence is unknown. Only one symptomatic patient (with anaemia, failure to thrive, dilated cardiomyopathy and plasma carnitine deficiency) has been described so far, but several series of patients have been identified through newborn screening programs relying on detection of increased C(4)-carnitine levels by tandem mass spectrometry. The disorder is caused by mutations in the ACAD8 gene (11q25).


A rare sex-chromosome anomaly characterized by various clinical presentations including normal healthy fertile males, male phenotype with infertility, and males with ambiguous genitalia or incomplete masculinization.


A rare sex-chromosome anomaly with a variable phenotype including a female phenotype with sexual development delay, streak gonads, short stature and Turner syndrome features, and a male phenotype with infertility due to azoospermia.


Isolated absence of both forearm and hand

Congenital absence of both forearm and hand is a rare developmental defect during embryogenesis characterized by unilateral or bilateral arrest of proximal to distal development of the upper limb, leading to a transverse deficiency with absence of the forearm, wrist and hand. A short below-the-elbow amputation is most commonly observed and the residual limb is usually well cushioned, with rudimentary nubbins or dumpling possibly found on the end.


Isolated absence of both lower leg and foot

Congenital absence of both lower leg and foot is a rare, non-syndromic, terminal transverse limb reduction defect characterized by unilateral or bilateral absence of both the tibia and the fibula, as well as the distal elements composing the foot.


Isolated absence of thigh and lower leg with foot present

Congenital absence of thigh and lower leg with foot present is a rare, non-syndromic, intercalary limb reduction defect characterized by unilateral or bilateral absence of femoral and tibio-fibular components, with the presence of intact foot elements.


Isolated absence of upper arm and forearm with hand present

A rare congenital limb malformation characterized by absence or marked shortening of the proximal to mid portion of an upper limb, while the hand is normal or nearly normal. The condition may be unilateral or bilateral, and occur sporadically or as part of a malformation syndrome.


Isolated absence/hypoplasia of fingers excluding thumb, unilateral

Congenital absence/hypoplasia of fingers excluding thumb, unilateral is a rare, non-syndromic, terminal transverse limb reduction defect characterized by unilateral absence of the terminal portions of digits 2 to 5, with a mildly hypoplastic thumb and small nail remnants on the digital stumps. Metacarpal bones may be variably reduced.


A rare non-syndromic limb reduction defect characterized by the congenital total absence of the hand and wrist with no bony elements distal to the radius or ulna. The malformation can be unilateral or bilateral.


An extremely rare developmental disorder characterized by bilateral, congenital and complete amputation of the distal extremities (amputation of distal epiphysis of the humerus, distal portion of the tibial diaphysis, aplasia of the radius, ulna, fibula) and aplasia of hands and feet (aplasia of carpal, metacarpal, tarsal, metatarsal and phalangeal bones). Rarely, an ectopic bone can be found at the distal end of the humerus. No other systemic manifestations have been reported and the disorder follows an autosomal recessive pattern of inheritance.


Isolated agammaglobulinemia (IA) is the non-syndromic form of agammaglobulinemia, a primary immunodeficiency disease, and is characterized by deficient gamma globulins and associated predisposition to frequent and recurrent infections from infancy.

Summary:
Epidemiology
Prevalence is estimated to be about 1/250,000 to 1/500/000. Isolated agammaglobulinemia has been reported worldwide in all ethnic groups.
Clinical description
Two forms of IA have been described based on the pattern of inheritance of the genetic defects underlying the disorder: X-linked agammaglobulinemia (XLA) which represents approximately 85% of the affected patients, and autosomal agammaglobulinemia (see these terms) which includes recessive and dominant cases but is far less frequent. The clinical signs of the two forms are very similar and include recurrent bacterial infections (otitis media, pneumonia, and sinusitis), diarrhea and skin infections with onset in infancy. Late-onset agammaglobulinemia is known as common variable immunodeficiency (CVID; see this term).
Etiology
Defects in B lymphocyte development and maturation appear to underlie agammaglobulinemia. Mutations in seven genes have been reported to be related to IA: BTK (Xq21.33-q22), BLNK (10q23.2-q23.33), CD79A (19q13.2), CD79B (17q23), IGHM(14q32.33), IGLL1 (22q11.23), PIK3R1 (5q13.1) and TCF3 (19p13.3).
Genetic counseling
X-linked, autosomal recessive and autosomal dominant cases are reported.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Dr Marie Ellen CONLEY


A rare biliary tract disease characterized by congenital absence of the gallbladder and cystic duct. The majority of patients are asymptomatic. Possible clinical manifestations include abdominal pain and tenderness in the right upper quadrant, nausea, vomiting, fatty food intolerance, and jaundice. Frequency of choledocholithiasis is increased significantly.


A rare, non-syndromic limb reduction defect characterized by complete or near-complete congenital absence of one (unilateral) or both (bilateral) of the lower extremities, occurring due to an intrauterine insult during the very early stages of embryonic development. It may be an isolated anomaly, but is more commonly observed in combination with multiple other congenital malformations.


A rare, non-syndromic limb reduction defect characterized by complete or near-complete congenital absence of one (unilateral) or both (bilateral) of the upper extremities, occurring due to an intrauterine insult during the very early stages of embryonic development. It may be an isolated anomaly, but is more commonly observed in combination with multiple other congenital malformations.


A rare central nervous system malformation characterized by congenital absence of the spinal cord, usually associated with segmental bony spinal anomalies. Neurologic deficits depend on the affected segments and the functioning of the residual spinal cord. Typically, the spinal cord appears normal above the defect and bulky, thickened, and low-lying caudally. Clinical presentation includes varying degrees of motor weakness (associated with deformities of the lower limbs) and neurogenic bladder dysfunction.


A neural tube defect. This malformation is characterized by the total or partial absence of the cranial vault and the covering skin, the brain being missing or reduced to a small mass. Most cases are stillborn, although some infants have been reported to survive for a few hours or even a few days.

Summary:
Epidemiology
Its prevalence at birth ranges from 1 in 5000 to 1 in 2000. The prevalence at birth displays an unequal geographical distribution, with especially high rates in the British Isles, China, Mexico and Turkey. This may be attributed to the genetic backgrounds of the populations and to dietary habits.
Etiology
Autopsy findings reveal that anencephaly is in most cases associated with absence of adrenal glands. Anencephaly is likely to be multifactorial, the result of gene-environment interactions. Folic acid and zinc deficiencies, as well as maternal obesity, have been shown to be risk factors.
Antenatal diagnosis
Prenatal diagnosis can be made easily by ultrasonography in the first trimester of pregnancy when the cranial vault is not yet apparent.
Genetic counseling
Familial cases with a seemingly autosomal recessive mode of inheritance have been described but most cases are sporadic.
Management and treatment
Prevention of recurrence for subsequent pregnancies should include prescription of 4 mg/day of folic acid, to be started before pregnancy and continued until the second missed period. For subsequent pregnancies there is also an increased risk of spina bifida.

                            Last update:
                            March 2006


Isolated aniridia is a congenital bilateral ocular malformation characterized by the complete or partial absence of the iris.

Summary:
Epidemiology
The annual incidence is estimated at 1/ 64,000- 1/ 96,000.
Clinical description
Isolated aniridia can occur in association with a range of other ocular anomalies including cataract, glaucoma (usually occurring during adolescence), corneal pannus, optic nerve hypoplasia, absence of macular reflex, ectopia lentis, nystagmus, and photophobia, all of which generally result in poor vision.
Etiology
Aniridia is due to mutations in the PAX6 gene (11p13) encoding a transcriptional regulator involved in oculogenesis. PAX6 mutations result in alterations in corneal cytokeratin expression, cell adhesion and glycoconjugate expression.
Diagnostic methods
Diagnosis is based on ophthalmological examination and is confirmed by mutation detection of the PAX6 gene.
Antenatal diagnosis
Antenatal diagnosis is only possible when the underlying genetic defect is known. It is performed by invasive procedures like chorionic villus sampling (CVS) or amniocentesis and molecular analysis of fetal DNA.
Genetic counseling
Aniridia is inherited in an autosomal dominant manner with high penetrance and variable expression. About two-thirds of affected children have an affected parent and one-third of cases occur in sporadic form.
Management and treatment
A regular follow-up is necessary. Intraocular pressure should be measured yearly for detection of glaucoma. Keratolimbal allograft (a stem cell transplantation technique) has been evaluated as a treatment of the aniridic keratopathy, which is a major cause of vision loss in aniridia patients. Glaucoma drainage is used to treat secondary angle closure glaucoma.
Prognosis
Aniridia results in poor vision, the mean visual acuity being around 0,19 in young adulthood.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Pr Michael PETERSEN


Isolated ankyloblepharon filiforme adnatum (AFA) is characterised by the presence of single or multiple thin bands of connective tissue between the upper and lower eyelids, preventing full opening of the eye. Several cases have been reported. It can occur sporadically or following an autosomal dominant transmission pattern. In some cases, AFA can be associated with other disorders, such as trisomy 18. The bands should be removed to avoid amblyopia and this can easily be performed in the neonatal period by cutting with tissue scissors.


Isolated anterior cervical hypertrichosis

A rare form of localised hypertrichosis characterized by hair growth near the laryngeal prominence during childhood.


A rare non-syndromic limb reduction defect characterized by congenital total absence of the foot and ankle with no bony elements distal to the tibia or fibula, while the lower leg, including the epiphysis of the tibia and fibula, is present. The malformation can be unilateral or bilateral.


Isolated arhinencephaly is a rare non-syndromic central nervous system malformation defined by the agenesis of the olfactory bulbs and tracts and characterized by complete congenital anosmia.


An extremely rare, major congenital malformation consisting of an absence of the nose ranging from hyporrhinia (absence of external nasal structures) to total arrhinia (absence of external nose, nasal airways, olfactory bulbs, or olfactory nerve) often causing respiratory distress and requiring surgical correction. Arrhinia can be bilateral or unilateral (hemiarrhinia). Associated anomalies include ocular features (hypertelorism, microphthalmia, eyelid coloboma), facial clefts, midline defects and microtia.


Isolated asymptomatic elevation of creatine phosphokinase

A rare neurologic biological anomaly characterized by persistent elevation of the serum creatine phosphokinase (CK) without any clinical, neurophysical or histopathological evidence of neuromuscular disease using the available laboratory procedures. It is usually an incidental finding, diagnosed after exclusion of other possible causes of elevated CK levels.


Isolated ATP synthase deficiency is a rare, genetic, mitochondrial oxidative phosphorylation disorder that may present with a wide range of symptoms (including muscular hypotonia, hypertrophic cardiomyopathy, psychomotor delay, encephalopathy, peripheral neuropathy, lactic acidosis, 3-methylglutaconic aciduria) and clinical syndromes (including NARP and MILS).


Isolated autosomal dominant hypomagnesemia, Glaudemans type (IADHG) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by low serum magnesium (Mg) values but normal urinary Mg values. The typical clinical features are recurrent muscle cramps, episodes of tetany, tremor, and muscle weakness, especially in distal limbs. The disease is potentially fatal.

Summary:
Epidemiology
IADHG has only been described in one large Brazilian kindred with 46 family members, of whom 21 were affected.
Clinical description
Onset of IADHG is typically in infancy. Clinical manifestations consist of recurrent and severe muscle cramps, episodes of tetany, tremor, and muscle weakness, especially in distal limbs. Additional features include facial myokymia, arythmias, severe muscle spasms and muscular pain.
Etiology
IADHG is caused by a N255D mutation in the KCNA1 gene (12p13), which encodes the voltage-gated potassium channel Kv1.1 (expressed in the kidney, where it colocalized with TRPM6 in apical membrane of distal convoluted tubule). Mutations in KCNA1 result in a nonfunctional channel protein, with a dominant negative effect on wild-type Kv1.1 channel function, which is involved in the maintenance of membrane voltage and optimal function of the TRPM6 channel.
Diagnostic methods
Diagnosis relies on laboratory findings showing low serum Mg levels, while serum potassium (K) and calcium (Ca) levels and urinary Ca excretion are not affected. Diagnosis is confirmed by genetic screening of KCNA1.
Differential diagnosis
Differential diagnosis includes the other forms of FPH and episodic ataxia type 1 (see these terms).
Genetic counseling
Transmission is autosomal dominant. Genetic counseling may be proposed and the recurrence risk is 50%.
Management and treatment
Management is mainly symptomatic and involves a daily dose of magnesium chloride. During manifestations, intravenous or intramuscular administration of magnesium sulfate is preferred.
Prognosis
Prognosis highly depends on rapidity of diagnosis and treatment, as the disease can be fatal following tetany attacks.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Rosa VARGAS-POUSSOU


Isolated bilateral hemispheric cerebellar hypoplasia is a rare cerebellar malformation characterized by hypoplasia of both cerebellar hemispheres with no other cerebellar/cerebral anomaly or other associated clinical feature. Affected patients present with mild hypotonia with motor delay, mild cognitive impairment, language delay, visuospatial and verbal memory deficits, dysdiadochokinesis, intentional tremor, and possible presence of emotional fragility and mild depression.


A rare, biliary tract disease characterized by progressive obliterative cholangiopathy of the intra- and extrahepatic bile ducts, occuring in the embryonic/ perinatal period, leading to severe and persistent neonatal jaundice and acholic stool.

Summary:
Epidemiology
Biliary atresia (BA) prevalence at birth is 1/ 15,000-19,000 in Europe and North America.
Clinical description
Diagnosis is mostly made at 2-6 weeks of age, presenting with cholestasis, jaundice, acholia and possibly choluria and hepatomegaly, and sometimes vitamin K deficiency induced bleedings. Conjugated hyperbilirubinemia associated with an increase in γ-glutamyltransferase (GGT) are biochemical signs of the disease. The pathology is characterized by an ongoing inflammatory process of the entire biliary tree, although the disease is defined as an irreversible closure/ atresia of the extrahepatic bile ducts. In 10-20% of cases, biliary atresia is associated with other malformations (syndromic biliary atresia).
Etiology
The etiology is yet to be explained, but it is believed that it can be the result of the interaction of genetic, environmental, immune, and infectious factors, individually or in combination.
Diagnostic methods
Preoperative evaluation may include abdominal ultrasound, hepatobiliary scintigraphy, percutaneous liver biopsy, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiopancreatography (MRCP). However, the definitive diagnosis is confirmed only by cholangiography.
Differential diagnosis
The differential diagnosis include other causes of neonatal cholestasis, for example infections, Alagille syndrome, alpha-1-antitrypsin deficiency, progressive familiar intrahepatic cholestasis (PFIC) and hormonal deficiencies.
Antenatal diagnosis
Signs of biliary atresia on prenatal ultrasonography has rarely been reported.
Genetic counseling
The disease is not yet identified to be hereditary. The genetic counseling is therefore not possible.
Management and treatment
Kasai portoenterostomy is the gold standard treatment, consisting in total extraction of the hilar fibrosis and subsequent biliary-enteric anastomosis, with favorable results in a maximum of 50% of cases, in which there is total restitution of the biliary drainage and normalization of total bilirubin levels.
Prognosis
The main prognostic factors to short- and long-term survival after surgery include age at surgery, type of biliary atresia, and experience of the center. Out of the possible complications, the most common are cholangitis, portal hypertension, and ongoing deterioration of the liver function with cirrhosis, leading to end-stage failure. Early liver transplantation is required in about 50% of the cases. Very long term survival with native liver decreases to about 25%.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Björn FISCHLER | RARE-LIVER* - Pr Claus PETERSEN | RARE-LIVER*

                                * European Reference Network


A rare palpebral disorder characterized by recurrent episodes of painless eyelid edema. It usually occurs bilaterally, typically affects the upper eyelids, and may manifest as a hypertrophic form resulting in orbital fat herniation through a weakened orbital septum, or an atrophic form with atrophy of redundant eyelid skin and superior nasal fat pads. Additional findings are formation of pseudoepicanthal folds, lacrimal gland prolapse, or ptosis.


A rare subtype of indolent systemic mastocytosis characterized by isolated bone marrow involvement without skin lesions, low burden of neoplastic mast cells, and often normal or near normal serum tryptase levels. The KIT D816V mutation is present in the majority of cases.


A rare non-syndromic central nervous system malformation characterized by complete or near-complete absence of the cerebellum with a normal sized posterior fossa, possibly accompanied by hypoplasia of the brainstem. The clinical picture is highly variable, but typically includes ataxia, dysarthria, tremor, dysmetria, dysdiadochokinesia, and oculomotor abnormalities, in addition to impaired mental, motor, and language development and intellectual disability.


A rare, congenital, cerebellar malformation disorder characterized by complete or partial cerebellar vermis agenesis, with no other associated malformations or anomalies. Patients may be asymptomatic, although psychomotor delay, hypotonia and incoordination are usually associated. Additional variable manifestations include intellectual disability, oculomotor abnormalities (such as nystagmus, impaired smooth pursuit, impaired saccades, strabismus, ptosis, and oculomotor apraxia), retinopathy, abnormal visual evoked potentials, ataxia, episodic hyperpnea, and delayed gait acquisition, as well as delayed speech and language development.


Isolated cerebellar vermis hypoplasia is a rare, non-syndromic cerebellar malformation characterized by an underdeveloped cerebellar vermis. Patients may present a variable phenotype ranging from normal neurodevelopment to motor and/or language delay, variable degrees of cognitive impairment, hypotonia, equilibrium disturbances, static/dynamic ataxia, oculomotor abnormalities, epilepsy and/or clumsiness. Behavioral disorders such as attention deficit hyperactivity disorder and generalized anxiety have also been reported. Brain MRI may reveal diffuse or selective (mostly posterior) vermian cerebellar hypoplasia and EEG may show focal paroxysms.


A rare neurologic disease characterized by impaired ability to execute complex coordinated movements underlying the production of speech, leading to highly unintelligible speech in the absence of muscular or sensory deficits.

Summary:
Epidemiology
The exact prevalence of isolated childhood apraxia of speech (CAS) is unknown. Regarding CAS due to FOXP2 variants, approximately 35 individuals from 11 families with intragenic, pathogenic variants have been described in the literature so far. Moreover, a few individuals with speech and language disorders and larger deletions on chromosome 7 including FOXP2 or other structural variants in or next to FOXP2 have been reported.
Clinical description
CAS is characterized by the impairment of the precision and consistency of movements underlying speech in the absence of neuromuscular deficits. Initial signs may include absence of babbling or delay of first words during infancy. Additional manifestations including dysarthria, oral motor dyspraxia, receptive and expressive language impairment, impairment of reading and spelling, global developmental delay, autistic features, and minor facial dysmorphism have been described occasionally for patients with CAS due to FOXP2 variants.
Etiology
The disorder may be idiopathic or due to FOXP2 (7q31.1) haploinsufficiency. FOXP2 (7q31.1) encodes forkhead box protein P2, a member of the forkhead box family of transcription factors. Usually, heterozygous missense variants within the forkhead domain or truncating variants are identified but also larger deletions containing FOXP2 or structural aberrations disrupting FOXP2 have been reported.
Diagnostic methods
Diagnosis is usually by targeted analysis upon clinical suspicion or by more unbiased approaches such as chromosomal microarray analysis (deletions including FOXP2), multigene panel or exome sequencing.
Differential diagnosis
Differential diagnosis includes syndromic disorders with overlapping, prominent speech and language impairment and a variety of additional clinical aspects (e. g. intellectual disability, epilepsy, growth phenotypes, malformations) and includes 7q31 microdeletion syndrome, 16p11.2 microdeletion syndrome, 7q11.23 duplication syndrome, KANSL1-related intellectual disability syndrome, and GRIN2A-related disorders. CAS, although mostly not isolated, can also occur secondary to intrauterine stroke, infections, or trauma.
Antenatal diagnosis
In principle possible, if the underlying pathogenic variant in the family is known.
Genetic counseling
Recurrence risk for siblings of an affected individual depends on the underlying cause of CAS. Recurrence risk for CAS due to FOXP2 alterations is low if the pathogenic variant occurred de novo and 50 % if it is inherited from one of the parents. Genetic counseling should be offered.
Management and treatment
A multidisciplinary team including a speech and language pathologist, a pediatrician, an occupational therapist, and a neuropsychologist is required for evaluation of the phenotypic extent and to determine the individual treatment plan. Augmentative and alternative communication (use of sign language, picture boards or computers) may be useful in some cases.
Prognosis
Prognosis depends on the underlying cause of CAS. It is usually good in the context of intragenic FOXP2 variants, as clinical aspects are limited to speech and language impairment in most cases. However, learning disabilities or behavioral abnormalities may additionally occur. Though speech development and intelligibility usually improve over time, a lifelong speech and language impairment might be present.

                            Last update:
                            May 2022

                            - Expert reviewer(s):
                            Dr Melissa RIEGER | ITHACA* - Pr Christiane ZWEIER

                                * European Reference Network


Isolated cleft lip is a fissure type embryopathy extending from the upper lip to the nasal base.

Summary:
Epidemiology
The annual incidence is 1/4,000 to 1/10,000 births with major variation occurring between geographic locations and ethnic groups. Cleft lip is twice as common in boys as girls and is seen more frequently on the left side.
Clinical description
The cleft is paramedian and located at the level of the philtrum. It presents as a cutaneous, muscular and mucosal interruption from the lip to the nasal base, associated with nostril and nasal septum deformations. Clinical forms range from a simple notch in the upper lip to a complete cleft lip with an opening at the base of the nostril without reaching as far as the gum (alveolar ridge).
Etiology
This embryopathy appears between the 5th and 12th week of pregnancy due to a failure in the fusion of the frontal processes (fronto-nasal process, medial and lateral nasal processes, maxillary process). Cleft lip is an isolated, non-syndromic anomaly in 70% of cases. The remaining 30% of cases are seen in at least 300 syndromes where cleft lip is just one of the featured anomalies. Non-syndromic clefts are possibly caused by a combination of genetic and environmental factors. Factors such as the exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can have an influence on genetic susceptibility.
Diagnostic methods
The diagnosis is clinical.
Differential diagnosis
The presence of associated malformations allows for differentiation between isolated and syndromic forms.
Antenatal diagnosis
Antenatal diagnosis is often possible with a prenatal ultrasound. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.
Management and treatment
Management requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery sometimes followed by secondary maxillo-facial and plastic surgery. An initial treatment timeline is established during the neonatal period. Secondary management is adapted to the child's age and based on morphological and functional problems that may arise during growth and development. Breathing difficulties can occur due to the nostril anomaly and the deviation of the vomer, of the nasal septum and to the turbinate hypertrophy. Secondary surgery of the nose can be performed to improve appearance and function.
Prognosis
Prognosis is dependent on the quality of initial management and the regular follow-up by an experienced interdisciplinary team until the child is fully grown. Cleft lip can have functional (morphological, respiratory), esthetic and psychological consequences that require management in a specialized health center.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ


Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms).


Isolated complex III deficiency is a rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by a wide spectrum of clinical manifestations ranging from isolated myopathy or transient hepatopathy to severe multisystem disorder (that may include hypotonia, failure to thrive, psychomotor delay, cardiomyopathy, encephalopathy, renal tubulopathy, hearing impairment, lactic acidosis, hypoglycemia and other signs and symptoms).


Isolated congenital adermatoglyphia is a rare, genetic developmental defect during embryogenesis disorder characterized by the lack of epidermal ridges on the palms and soles, resulting in the absence of fingerprints, with no other associated manifestations. It is associated with a reduced number of sweat gland openings and reduced transpiration of palms and soles.


Congenital alacrima is characterised by deficient lacrimation (ranging from a complete absence of tears to hyposecretion of tears) that is present from birth.

Summary:
Epidemiology
Prevalence is unknown.
Genetic counseling
Transmission is usually autosomal recessive, but dominant transmission has also been described.
Management and treatment
Artificial tears are the first treatment option, needed to avoid corneal sequelae.

                            Last update:
                            April 2007


Isolated congenital anonychia is characterized by nail abnormalities ranging from onychodystrophy (dystrophic nails) to anonychia (absence of nails). Onychodystrophy-anonychia has been described in at least four generations of a family with male-to-male transmission, suggesting autosomal dominant transmission. Anonychia has been described in approximately less than 20 cases; it is likely to be transmitted as an autosomal recessive trait. Total anonychia congenita, in which all the fingernails and toenails are absent, may have an autosomal dominant inheritance pattern.


A rare otorhinolaryngologic disease characterized by total or partial anosmia at birth. The anosmia is caused by a defect in the development of the olfactory bulbs or by replacement of the olfactory epithelium by respiratory epithelium. Isolated congenital anosmia is found in some parents of individuals with Kallman syndrome.


Isolated congenital auditory ossicle malformation is a rare, congenital, middle ear anomaly characterized by, usually unilateral and sporadic, variations in the number, size and/or configuration of the ossicles, with no tympanic membrane and external ear abnormalities and no history of trauma or infection. Patients frequently present late, after schooling has started, with non-progressive, conductive hearing loss often associated with speech delay and poor school performance.


Isolated congenital breast hypoplasia/aplasia

A rare breast malformation characterized by congenital absence of breast and nipple (amastia), or nipple or mammary gland (athelia or amazia, respectively). It can be unilateral or bilateral and may occur as an isolated malformation or be associated with a syndrome or cluster of other anomalies.


Isolated congenital ectropion is a rare ocular disease characterized by congenital, unilateral or bilateral, lower or upper eyelid malposition with eversion of the margin due to a vertical shortage of skin, leading to exposure of the conjunctiva and sometimes the cornea. Chronic epiphora and exposure keratitis may be observed in severe cases.


A rare eyelid malposition disorder characterized by congenital abnormal inversion of the eyelid towards the globe, potentially causing mechanical irritation of the ocular surface by the eyelashes, which may lead to corneal abrasion and scarring with visual impairment. Typical initial symptoms are foreign body sensation, redness, tearing, and ocular discharge.


A rare parenchymal liver disease characterized by progressive fibrosis of the portal tracts due to arrest of maturation of the ductal plate of the intrahepatic bile ducts. Clinically, it may manifest as a portal hypertensive, cholangitic, mixed, or latent form. Onset of symptoms is mostly in adolescence or young adulthood. Hepatocellular function is relatively well preserved.


A rare head and neck malformation characterized by congenital partial (hypoglossia) or total (aglossia) absence of the tongue. Patients present feeding and respiratory difficulties, as well as delayed speech development and slurred speech. Taste perception is not severely compromised. Associated features include a characteristic facies due to mandibular transverse arch deficiency, oligodontia, and malocclusion, among others.


Isolated congenital hypogonadotropic hypogonadism

A rare, genetic pituitary hormone deficiency characterized by gonadotropin (Gn) deficiency with low sex steroid levels associated with low levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH). This disorder may be associated with a normal (normosmic) or impaired sense of smell (Kallmann syndrome).

Summary:
Epidemiology
Exact prevalence is unknown but is estimated to be between 1/5,000 and 1/10, 000.
Clinical description
Congenital hypogonadotrophic hypogonadism (CHH) is isolated when the deficiency is restricted to the gonadotrope axis. Diagnosis is typically during adolescence due to the absence or incomplete pubertal development although it may be suspected at birth in males with micropenis (often associated with cryptorchidism). Later diagnosis during adulthood is possible, but less frequent, as a result of infertility. Isolated CHH can be associated with normal sense of smell (normosmic CHH) or anosmia/hyposmia with hypoplasia or aplasia of the olfactory bulbs (Kallmann syndrome). Untreated adult males exhibit absent or reduced virilization and usually have decreased bone density and muscle mass, decreased testicular volume (< 4 mL), erectile dysfunction, diminished libido and infertility. Untreated adult females almost always experience primary amenorrhea with absent, little or even normal pubic hair and breast development. Kallmann syndrome may be associated with addition anomalies including sensorineural deafness, renal agenesis and midline defects.
Etiology
Isolated CHH is the result of the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), the master hormone regulating the reproductive axis. This is frequently due to failure of GnRH neurons in the hypothalamus to differentiate, develop (Kallmann syndrome) or secrete GnRH. In a subgroup of patients, the defect is due to GnRH resistance in pituitary gonadotropic cells (e.g. loss of function mutations in the GnRH receptor). Many genes have been implicated in the pathogenesis.
Diagnostic methods
Diagnosis is based on clinical evaluation of the hypogonadism and hormone testing to confirm gonadotropin deficiencies (FSH and LH) caused by GnRH deficiency. Laboratory tests should be performed either in the first six months of life or after 12-13 years of age. Further investigations may include familial and patient history, tests for anosmia and hearing loss, and MRI for identifying olfactory bulb and/or sulcus anomalies. However, the current increased use of next generation sequencing (targeted exome) in clinical practice allows the identification of causative genes without necessarily completing an exhaustive search for associated signs.
Differential diagnosis
Differential diagnoses should include other causes of micropenis and cryptorchidism at birth (syndromic or isolated), transitory hypogonatorphic-hypogonadism (associated with constitutional delay of growth and puberty), functional hypogonatorphic-hypogonadism associated with caloric restriction or undernutrition, hypothyroidism, and secondary causes of HH (hypothalamic-pituitary tumors / adenomas or infiltrations (iron overload), surgical or radiation therapy-induced sequelae, as well as other endocrine diseases).
Antenatal diagnosis
Fetal ultrasound monitoring of anomalies associated with Kallmann syndrome may be useful but genetic prenatal diagnosis is generally not considered because of the good prognosis and the usual absence of major disability.
Genetic counseling
The inheritance patterns of congenital hypogonadotropic hypogonadism vary and include X-linked recessive, autosomal recessive, autosomal dominant, oligogenic as well as sporadic forms. Genetic counseling should be offered accordingly.
Management and treatment
CHH is one of the rare treatable causes of male infertility. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the possible psychological effects. In most cases, fertility can be induced using specialized treatment regimens, best deployed in a reference center, and patients typically require life-long treatment and monitoring in order to maintain sexual function and secondary sexual characteristics, although ~10-20% of patients exhibit a spontaneous recovery of reproductive function and some men seem to sustain reversal of the disease after discontinuation of hormonal therapy.
Prognosis
The prognosis is generally good, with the outcome for fertility depending, particularly in affected males, on the severity of the sex hormone deficiency and the age of initiation of treatment. Rare cases of complete resolution have been described.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Pr Jacques YOUNG


A rare laryngeal malformation characterized by a membrane-like structure of variable thickness that extends across the laryngeal lumen, between the vocal cords.

Summary:
Epidemiology
The worldwide prevalence is unknown. Congenital laryngeal web represents fewer than 5% of congenital laryngeal anomalies.
Clinical description
Manifestations may appear at any age (mostly with hoarse or weak voice) but onset usually occurs during infancy (respiratory distress, stridor and an unusual cry). Clinical manifestations and their severity vary with the extent of obstruction and glottic involvement. Webs are categorized in the Cohen classification on the basis of glottic involvement. Type 1 are thin webs with <35% of glottic involvement. Type 2 are webs with 35-50% of glottic involvement. Type 3 are webs with 50-75% of glottic involvement and subglottic stenosis due to anterior cricoid cartilage extension; type 4 are webs with 75-90% of glottic involvement and subglottic stenosis due to anterior cricoid cartilage extension. Other larynx anomalies, such as laryngeal cleft and congenital subglottic stenosis, may be associated with this malformation.
Etiology
The malformation is a result of anomalous embryologic development of the larynx, stemming from incomplete resorption of the epithelial layer that normally obliterates the developing laryngeal opening at about the sixth week of gestation. This layer is usually completely eliminated by the tenth week. Since resorption proceeds from the dorsal to the ventral side, laryngeal webs are anteriorly located, leaving a posterior lumen. Although no gene was been specifically identified as the cause for this malformation, over half of the patients present with a syndromic form of the disease caused by a chromosome 22q11.2 deletion. Other genetic syndromes may also be associated with this malformation.
Diagnostic methods
Diagnosis of congenital laryngeal web is based on clinical signs (dysphonia, respiratory distress) and laryngeal endoscopy. A significant part of the patients presents with comorbidities such as chromosomal and cardiovascular anomalies. Patients should undergo genetic screening, which must include testing for a chromosome 22q11 deletion, and a thorough cardiovascular evaluation, which should include imaging of the aortic arch.
Differential diagnosis
Apart from syndromic forms linked to 22q11.2 deletion syndrome, the differential diagnosis includes laryngeal congenital complex stenosis, laryngeal papillomatosis, and subglottic cysts.
Genetic counseling
Genetic counseling with testing for 22q11 deletion is highly recommended. The mode of inheritance is autosomal dominant and families should be informed that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
The primary goals of treatment are to provide a patent airway and to achieve a good voice quality. However, vocal cords have a tendency for restenosis, fibrosis and granulation tissue formation after a surgical procedure and notably at their anterior part, where the web is usually located. The management and treatments range from surveillance (for small and thin web with no effect on ventilation and no or light dysphonia) to endoscopic section with cold instruments or laser. A laser should be used carefully because of the alleged extra scarring the burns induce, increasing the risk of restenosis. Good voice quality is mainly achieved in patients with thin, membranous, uncomplicated webs. Treatment for thick webs, with or without associated congenital subglottic stenosis, remains unsatisfactory. Thick webs can be assimilated to congenital laryngeal stenosis, and therefore treated by endoscopic section but above all laryngoplasty by external approach and stenting.
Prognosis
The laryngeal prognosis is usually good even if the dysphonia may not disappear totally over time.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Pr Nicolas LEBOULANGER | ERN CRANIO* - Dr Roman LUSCAN | ERN CRANIO* - Dr Briac THIERRY | ERN CRANIO*

                                * European Reference Network


Isolated congenital megalocornea is a genetic, non-syndromic developmental defect of the anterior eye segment characterized by bilateral enlargement of the corneal diameter (>12.5 mm) and a deep anterior eye chamber, without an elevation in intraocular pressure. It can manifest with mild to moderate myopia as well as photophobia and iridodonesis (due to iris hypoplasia). Associated complications include lens dislocation, retinal detachment, presenile cataract development, and secondary glaucoma.


A rare neurological disorder characterized by a reduced head circumference at birth with no gross anomalies of brain structure. It can be an isolated finding or it can be associated with seizures, developmental delay, intellectual disability, balance disturbances, hearing loss or vision problems.


Isolated congenital nasal pyriform aperture stenosis

A rare otorhinolaryngological malformation characterized by narrowing of the pyriform aperture (i. e. < 8 to 10 mm in a full-term infant) due to an overgrowth of the nasal process of the maxilla, resulting in potentially lethal nasal airway obstruction in the newborn. Depending on the degree of obstruction, clinical signs and symptoms include inspiratory stridor, respiratory distress, cyanosis, sternal retraction, ribcage asymmetry, and feeding difficulties.


A rare isolated nail anomaly characterized by congenital unilateral or bilateral nail dysplasia (including micronychia, polyonychia, anonychia, hemionychrogryphosis, and malalignment) commonly involving the index fingers and/or other fingers or also toes, frequently associated with bony anomalies of the affected digits (such as Y-shaped bifurcation of the distal phalanx, brachymesophalangy, or syndactyly). The condition can be sporadic or familial.


Isolated congenital radial head dislocation

A rare congenital limb malformation characterized by mostly posterior, less frequently also anterior or lateral dislocation of the radial head from its position in the humeroradial joint. It is bilateral in the majority of cases and can occur as an isolated feature or in association with other congenital malformations and as part of a number of syndromes. The defect may at first cause only mild symptoms such as pain and limitation of flexion of the elbow, but may eventually lead to joint instability, dysplastic changes of the radial head, and arthritis.


A rare corneal disorder characterized by non-inflammatory, non-progressive, bilateral ingrowth of vascularized, opaque scleral tissue into the peripheral cornea, obliterating the corneoscleral limbus and scleral sulcus. The condition is not associated with other ocular abnormalities.


Isolated congenital syngnathia is a very rare developmental defect during embryogenesis disorder characterized by varying degrees of congenital fusion (ranging from simple mucosal adhesions to extensive bony fusion) of mandible to maxilla that is not associated with any other malformations. Patients present with mouth opening limitation (which could range from severe to minimal restriction) that typically results in feeding, swallowing and/or respiratory difficulties which may lead to failure to thrive, malnutrition and/or temporomandibular joint ankylosis.


A rare non-syndromic cerebral malformation characterized by congenital partial or complete absence of the corpus callosum. Patients are often asymptomatic but may also present with intellectual disability, visual impairment, delayed speech development, seizures, feeding difficulties, impaired hand-eye coordination, and behavioral abnormalities. Patients may have a normal intelligence quotient while exhibiting specific cognitive deficits, such as reduced interhemispheric transfer of sensorimotor information, reduced cognitive processing speed, and deficits in complex reasoning and novel problem-solving.


A rare congenital abnormality in which the eyelids are absent and skin covers the ocular bulb, which is often microphthalmic. A few cases of complete bilateral crytophthalmia have been described.


Isolated cytochrome C oxidase deficiency

A rare mitochondrial oxidative phosphorylation disorder characterized by a highly variable clinical phenotype, including a benign infantile mitochondrial type affecting mainly the skeletal muscle, a lethal infantile mitochondrial myopathy linked to severe metabolic acidosis and mitochondrial dysfunction in skeletal muscle and often also in heart, Leigh syndrome, which causes severe, early-onset, progressive, and fatal encephalopathy, and French-Canadian type Leigh syndrome, which affects mostly the skeletal muscle, but also brain and liver.


A rare non-syndromic central nervous system malformation characterized by the association of three signs: hydrocephalus, partial or complete absence of the cerebellar vermis, and posterior fossa cyst contiguous with the fourth ventricle, presenting early in life with hydrocephalus, bulging occiput and posterior fossa signs such as cranial nerve palsies, nystagmus and ataxia.


Isolated delta-storage pool disease is a rare, isolated, constitutional thrombocytopenia disorder characterized by defective formation and/or malfunction of platelet dense granules, as well as melanosomes in skin cells, resulting in variable manifestations ranging from mild bleeding and easy bruising to moderate mucous/cutaneous hemorrhagic diathesis and bleeding complications after surgery.


Distal symphalangism is a very rare bone disorder characterized by ankylosis of the distal interphalangeal joints of the hands and/or feet.


Isolated distichiasis is a rare congenital eyelid anomaly characterized by an accessory row of eyelashes (that may be partial or complete) posterior to the normal row of cilia, at or close to the meibomian gland orifices, that is not associated with any other condition, and that may lead to ocular irritation and corneal damage if left untreated.


Isolated ectopia lentis (IEL) is a rare, clinically variable, eye disorder characterized by dislocation of the lens, often causing significant reduction in visual acuity.

Summary:
Epidemiology
The prevalence of IEL is not known. About 90 cases have been reported to date, primarily in Europeans.
Clinical description
Patients with IEL are found to have dislocation of the lens, which may present at any age, but may be present from birth. Dislocation of the lens can be very mild leading to late diagnosis. In more severe cases, the anomaly is generally detected earlier with a greater impact on visual acuity. Lens dislocation may be progressive. Some patients are also found to have displacement of the pupils, usually in the opposite direction to lens displacement (known as ectopia lentis et pupillae). Other findings include congenital abnormalities of the iris, spherophakia, enlarged iris processes leading to abnormal iridocorneal angle, iridodonesis, lens coloboma, refractive errors (hyperopia, myopia, astigmatism), and early-onset cataract. They may develop amblyopia. Increased intraocular pressure (20%-25% of cases), retinal detachment and glaucoma may also befound. Ocular findings vary widely within families, and between the eyes in an affected individual. Visual acuity is variable depending on the severity of ocular anomalies and complications, ranging from light perception to 20/20 vision. IEL does not involve systemic abnormalities.
Etiology
Dislocation of the lens is the result of a loss of zonular fibers. Recessive mutations in the ADAMTSL4 (1q21.2) gene and dominant mutations in FBN1 gene (15q21.1) have been reported to cause IEL. Mutations in the former are thought to be the most important cause of this condition in Europeans. The exact function of these genes has not been clearly established. ADAMTSL4 mutations appear to manifest as a more severe, earlier onset condition than FBN1 mutations.
Diagnostic methods
Diagnosis is based on typical ocular findings through ophthalmologic examination and can be confirmed by molecular genetic testing of the causative genes.
Differential diagnosis
Patients with IEL by definition do not have associated systemic abnormalities, although cardiac and skeletal examinations should be performed to help exclude Marfan syndrome (diagnosed according to the Ghent criteria) (see this term). Ectopia lentis is also a feature of homocystinuria, sulfite oxidase deficiency, Weill-Marchesani syndrome, aniridia, and Knobloch syndrome (see these terms), as well as pseudoexfoliation.
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutations in the family have been identified.
Genetic counseling
ADAMTSL4-related IEL is inherited in an autosomal recessive manner. FBN1-related IEL follows an autosomal dominant pattern of inheritance.
Management and treatment
Visual acuity, refractive error, and intraocular pressure should be monitored regularly in affected patients. The primary aim of treatment in children is to prevent amblyopia through early correction of refractive errors. Surgical intervention may be considered by experienced ophthalmic surgeons. Lensectomy may be considered in patients with cataracts, in cases where the ectopic lens affects vision significantly. Treatment of the resulting aphakia may be with contact lenses. Alternatively, an intraocular lens (IOL) may be inserted in the anterior chamber, and sutured or glued into the posterior chamber or into the capsule, if it has been preserved during surgery. Complications include loss of accommodation, secondary glaucoma, and retinal detachment. A standard approach should be adopted in cases of retinal detachment. All patients found to have mutations in FBN1 should have regular cardiac examinations.
Prognosis
Visual prognosis depends on the degree of lens dislocation, the age of onset, age of treatment and complications.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Dr Aman CHANDRA


A rare, neural tube closure defect characterized by partial lacking of bone fusion, resulting in sac-like protrusions of the brain and the membranes that cover it through the openings in the skull. Protruding tissue may be located on any part of the head, but most often affects the occipital area. Depending in the size and location, encephalocele are often associated with neurological problems including intellectual disability, seizures, vision impairment, ataxia, and hydrocephalus.


A congenital genitourinary malformation belonging to the spectrum of the exstrophy-epispadias complex (EEC) and is characterized in males by an ectopic meatus or a mucosal strip in place of the urethra on the penile dorsum and in females by bifid clitoris and a variable cleft of the urethra.

Summary:
Epidemiology
The prevalence at birth for the EEC is reported at 1/10,000. As epispadias (E), classic bladder exstrophy (CEB) and cloacal exstrophy (EC) are now recognized clinical variants of the same spectrum, accurate epidemiological data on E/EC/CEB are no longer available. The malformation is likely underdiagnosed in females but the adjusted male-to-female ratio is estimated at 1.4:1.
Clinical description
Epispadias is usually recognized at birth, but the most distal forms, presenting with only minor clinical anomalies, maybe overlooked at birth, particularly in females. Epispadias in males can be classified as either penopubic, penile or glanular depending on the location of the meatus. Dorsal chordee is observed in all cases, although the degree varies. In females, epispadias can be severe (with a cleft involving the whole urethra and the bladder neck, together with bladder mucosal prolapse), intermediate, or mild (with a gaping meatus). The abdominal wall, rectus and umbilicus are normal and pelvic and pelvic floor anomalies are mild or absent. Urinary incontinence is the main clinical symptom in both sexes, ranging from urine permanently dripping through the meatus in severe forms, to involuntary urine loss with stress (coughing and strenuous effort) in milder forms. Urinary incontinence may not be observed in patients with the most distal forms of epispadias.
Etiology
Epispadias results from an anomaly during early embryologic development associated with abnormal partitioning of the cloacal membrane causing displacement of the genital tubercle and resulting in nonclosure of the urethral plate and an abnormal dorsal urethral location. The underlying cause remains unknown: both genetic and environmental factors are likely to play a role.
Diagnostic methods
Diagnosis is usually clinical. During follow-up, imaging studies (such as cystoscopy voiding cystography and urodynamics) are useful to determine the extent of the malformation.
Differential diagnosis
The typical clinical picture does not generally implicate any further differential diagnosis; however, epispadias is also a feature of the whole EEC spectrum (see this term).
Antenatal diagnosis
Prenatal diagnosis by ultrasound examination is very rare in patients with isolated epispadias due to the minor ultrasound features.
Management and treatment
Management is surgical, aiming for adequate cosmetic and functional genital reconstruction and, if necessary, achieving urinary continence. Several surgical approaches have been described for correction of epispadias in males involving meticulous partial or complete disassembly of the penis to allow correction of the dorsal chordee, urethral reconstruction for micturition and semen transport, glandular reconstruction and penile skin closure. Readaptation of the external sphincter and pelvic floor musculature or a complete bladder neck procedure may be required to achieve urinary continence. In females, genital reconstruction includes tubularization and correct placement of the distal urethra, as well as longitudinal closure of the cleft to fuse the labia and bifid clitoris, and, if necessary, skin and tissue reconstruction of the mons pubis area. After reconstructive surgery of the penis, adequate cosmetic and functional outcome can be expected. If a bladder neck procedure was necessary, continence rates are about 80% during childhood. In females, the genital defect is judged to be minor, mostly resulting in excellent cosmetic outcomes. In puberty, genital and reproductive function constitute increasingly important issues for both sexes.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr Anne-Karoline EBERT  - Dr Michaël LUDWIG  - Pr Heiko REUTTER  - Pr Wolfgang RÖSCH


Congenital short femur is a rare malformation of variable severity ranging from mild hypoplasia to complete absence of the femur.


A rare congenital limb malformation characterized by complete or partial absence of the fibula bone combined with dysplasia and hypoplasia of the tibia and dysplasia, hypoplasia or aplasia of parts of the foot.

Summary:
Epidemiology
Fibular hemimelia incidence is reported to be between 1/50,000 and 1/135,000 births. A slight male preponderance has been reported in some studies, whereas other reports describe an equal sex distribution.
Clinical description
Unilateral involvement is found in most cases. Bilateral fibular hemimelia is rare. Fibular hemimelia may vary from partial absence of the fibula with mild shortening and a relatively normal-appearing limb, to absence of the fibula with severe shortening and pro-curvatum of the tibia, knee joint instability and foot and ankle deformity. The foot frequently shows deficiency of the lateral rays with or without tarsal coalitions, and an equinovalgus position. Clubfoot-type fibular hemimelia presents with a clubfoot-like foot deformity. Shortening of the leg results from a constant growth inhibition that allows for prediction of leg length discrepancy at maturity. In many cases, fibular hemimelia is associated with congenital femoral deficiency of the femur (CFD), which can be very mild with only mild shortening and distal femur valgus. Most cases do not show any additional anomalies or other birth defects. In rare cases other skeletal anomalies (craniosynostosis, syndactyly, brachydactyly, oligodactyly and ectrodactyly) may be present. Fibular hemimelia can also be found in generalized skeletal dysplasias and dysostoses. Very rarely, fibular hemimelia is associated with non-skeletal malformations (eye abnormalities such as anterior chamber anomalies or anophthalmia, cardiac anomalies, renal dysplasia, thrombocytopenia, thoracoabdominal schisis, spina bifida).
Etiology
The etiology is unclear. The deformity is probably due to disruptions during the critical period of embryonic limb development, between 4th and 7th week of gestation. A somatic gene mutation has been suggested.
Diagnostic methods
Diagnosis is based on clinical examination and X-rays.
Differential diagnosis
Differential diagnoses include skeletal dysplasias and dysostoses with asymmetrical involvement of the lower limbs such as femoral-facial syndrome.
Antenatal diagnosis
Prenatal diagnosis of fibular hemimelia has been reported. The rate of true positive prenatal diagnosis is depending on the severity of shortening and the presence of foot anomalies like absent rays or clubfoot.
Genetic counseling
Most cases are sporadic. A family history has been reported in a small percentage of cases with an autosomal dominant pattern of inheritance and incomplete penetrance.
Management and treatment
Management requires a multidisciplinary approach (genetic counselors, pediatric orthopedic surgeons,). Orthopedic treatment aims at correcting the leg length discrepancy, and, in bilateral cases, correcting the asymmetrical dwarfism. However, the functional outcome in more severe cases is primarily depending on correction and management of the deformities and anomalies at the knee and foot and ankle. In less severe cases with minimal hypoplasia of the fibula and a stable knee and foot and ankle, simple bone lengthening is used to equalize limb length. In moderate to severe fibular hemimelia, limb lengthening needs to be combined with a correction of the complex deformities at the foot and ankle. If instability at the knee joint is clinically significant it also needs to be addressed with reconstructive procedures. Very rarely, for cases with most severe shortening and a non-functional foot, amputation with prosthetic fitting in early childhood may be considered. However, even then tibial procurvatum and knee flexion contracture need to be addressed.
Prognosis
Fibular hemimelia is usually a benign condition, although severe cases might need multiple surgeries throughout childhood. The functional result mostly depends on the status or quality of reconstruction of the knee and foot and ankle. In case of syndromic presentation, prognosis depends on the nature of the associated anomalies.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Sebastian FARR  - Pr Christof RADLER


Isolated focal cortical dysplasia is a rare, genetic, non-syndromic cerebral malformation due to abnormal neuronal migration disorder characterized by variable-sized, focalized malformations located in any part(s) of the cerebral cortex, which manifests with drug-resistant epilepsy (usually leading to intellectual disability) and behavioral disturbances. Abnormal MRI findings (e.g. abnormal white and/or grey matter signal, blurred gray-white matter junction, localized volume loss, cortical thickening, abnormal gyral pattern, abnormal hippocampus) and variable histopathologic patterns are associated.


Isolated focal non-epidermolytic palmoplantar keratoderma

A rare hereditary palmoplantar keratoderma characterized by focal hyperkeratotic lesions on the palms and soles. Histopathologic examination reveals prominent hyperkeratosis, thickened stratum spinosum with reduced stratum granulosum, disadhesion of cells in the suprabasal layers, elongation of rete ridges, and sparse lymphocyte infiltration in the dermis.


Isolated follicle stimulating hormone deficiency

A rare congenital hypogonadotropic hypogonadism characterized by hypogonadism due to selective deficiency of follicle stimulating hormone (FSH). Clinical manifestations are primary amenorrhea, absent or incomplete breast development, and infertility in women, and small testes, azoospermia, and infertility in men. Luteinizing hormone is elevated in the gonadotropin-releasing hormone stimulation test, while the FSH response is impaired.


A rare macular disorder characterized mostly by a variable degree of decreased visual acuity, jerk or pendular nystagmus, and typical ocular findings at imaging. The disease is usually bilateral. Rarely, nystagmus can be absent. Locally, the disease is characterized by underdeveloped foveal pit, absence of foveal pigmentation and/or foveal avascular zone, and persistence of inner retinal layers at the fovea, in absence of concomitant ocular or systemic pathology.


Isolated generalized anhidrosis with normal sweat glands

A rare genetic skin disease characterized by congenital generalized anhidrosis resulting in severe heat intolerance, due to functionally impaired eccrine sweat production. Skin biopsy reveals normal morphology and number of sweat glands. Dental, hair, nail, or other skin or extracutaneous anomalies are absent.


Isolated glycerol kinase deficiency (GKD) is a very rare X-linked disorder of glycerol metabolism characterized biochemically by elevated plasma and urine glycerol levels, and clinically by variable neurometabolic manifestations, depending on the age of onset, and varying from a life-threatening childhood metabolic crisis to an asymptomatic adult form (infantile GKD, juvenile GKD, and adult GKD (see these terms)).


Isolated hemihyperplasia is a rare overgrowth syndrome characterized by an asymmetric regional body overgrowth, involving at least one limb, and associated with an increased risk of developing embryonal tumors, principally nephroblastoma (see this term) and hepoblastoma.


Isolated hereditary congenital facial paralysis (IHCFP) is an extremely rare neurological disorder presumed to result from maldevelopment of the facial nucleus and/or cranial nerve and has been reported in fewer than 10 families to date. It manifests as non-progressive, isolated, unilateral or bilateral, symmetrical or asymmetrical facial palsy. Involvement of the branches of the facial nerve can be unequal.


Humeral agenesis/hypoplasia is a rare, non-syndromic limb reduction defect characterized by the unilateral or bilateral presence of a short arm with completely absent or underdeveloped humerus, frequently associated with ulnar and/or radial malformations. Patients may present with the appearance of the forearm directly attached to the shoulder, no articulation at the shoulder joint, impossible passive extension of the arm beyond the mid-axillary line, no elbow joints, bowing of the radius, a short ulna and/or ulnar/radial deviation of the hand at the wrist.


Humero-radial synostosis is a rare, genetic, congenital joint formation defect disorder characterized by uni- or bilateral fusion of the humerus and radius bones at the elbow level, with or without associated ulnar and carpal/metacarpal deficiency, leading to loss of elbow motion and, in many cases, functional arm incapacity. Bowing of radius may be additionally present.


Humero-radio-ulnar synostosis is an extremely rare, genetic, congenital joint formation defect disorder characterized by uni- or bilateral fusion of the humerus, radius and ulnar bones, leading to loss of elbow motion and, in most, functional arm incapacity. It may appear as distal humeral bifurcation with absent elbow joint and shortened arm length on imaging. Hand abnormalities, namely oligoectrosyndactyly, may be associated.


A rare joint formation defect characterized by a bony connection between the humerus and the ulna, resulting in fixed flexion of the forearm, usually near 90°. The condition may be associated with upper limb hypoplasia. It may be sporadic or familial and occur uni- or bilaterally.


A rare genetic skin disease characterized by excessive salt wasting in sweat, leading to hyponatremic dehydration, hyperkalemia, and poor feeding and slow weight gain in infancy. Laboratory examination shows hyponatremia, hyperkalemia, increased aldosterone, and increased sweat chloride concentrations.


Hyperphalangy is a congenital, non-syndromic limb malformation characterized by the presence of an accessory phalanx between metacarpal/metatarsal and proximal phalanx, or between any two other phalanges of a digit, excluding the thumb. Hypherphalangy is almost always bilateral and patients present no more than five digits and no other skeletal anomalies.


A rare congenital malformation characterized by underdevelopment of the thumb, ranging from a slight decrease in thumb size to complete absence of the thumb. The malformation may occur isolated, combined to other defects of the hand or upper limb, or as part of a multiple congenital anomaly syndrome.


A rare disorder of the anterior segment of the eye characterized by spontaneous separation of the anterior layer of the iris stroma from the posterior stroma and muscle layers. The anterior layer then splits into strands, and the free ends float freely in the anterior chamber. The condition usually affects patients in the seventh decade of life and is often associated with glaucoma. It may begin on one side but is typically a bilateral disease. The inferior part of the iris is most commonly involved.


Klippel-Feil Syndrome is characterised by improper segmentation of cervical segments resulting in congenitally fused cervical vertebrae.

Summary:
Epidemiology
The prevalence has been estimated at 1 in 50,000.
Clinical description
The syndrome was first reported in 1912 by Maurice Klippel and André Feil and is often associated with the classic clinical triad of manifestations consisting of a low posterior hairline, short neck, and limited neck range of motion. However, subsequent studies have shown that only 34% to 74% of patients present with such findings. The phenotypic expression of Klippel-Feil syndrome is variable, occurring with or without extraskeletal manifestations or any additional spinal abnormalities.
Etiology
The syndrome is caused by failure of cervical segmentation in the early stages of pregnancy but the exact aetiology and mode of inheritance remain unknown.
Diagnostic methods
Lateral neutral and flexion-extension as well as anteroposterior plain cervical radiographs demonstrating congenitally fused vertebrae are diagnostic. Magnetic resonance imaging and computed tomography can assist in the diagnosis and be used to evaluate for associated abnormalities.
Differential diagnosis
Differential diagnosis should include a surgical history of spinal fusion, ankylosing spondylitis, juvenile rheumatoid arthritis, fibrodysplasia ossificans progressiva (see these terms), and active or "burned out'' osteomyelitis.
Management and treatment
Treatment is based on the management of commonly associated symptoms, which include neck pain, radiculopathy, and/or myelopathy. The mainstay of treatment for patients with predominantly neck pain is conservative, non-operative measures. Radiculopathy secondary to nerve root impingement is also managed initially with conservative interventions and in selected cases may include spinal injections. Myelopathy due to spinal cord compression is typically attributed to congenital cervical stenosis, but may be exacerbated secondary to spinal cord compression from a combination of vertebral osteophyte and/or soft tissue compression. Patients with extensive congenital cervical fusion and/or excessive motion at a non-fused motion segment are regarded as being at high-risk for spinal cord injury and should alter daily activities to limit such potential injury. Surgical intervention may be warranted for specific cases where excessive cervical or craniovertebral motion is deemed potentially unstable and is associated with an increased risk of spinal cord injury.
Prognosis
The prognosis is variable.

                            Last update:
                            June 2007

                            - Expert reviewer(s):
                            Dr Dino SAMARTZIS  - Pr Francis SHEN


Isolated lissencephaly type 1 without known genetic defects belongs to the genetically heterogeneous group, classic lissencephaly (see this term). It is a diagnosis of exclusion, when neither associated malformations nor family history are present, and in the absence of mutations of genes known to be involved in classic lissencephaly. Clinically patients present with the common features of classic lissencephaly such as developmental delay, intellectual disability, and seizures.


A rare ophthalmic disorder characterized by an abnormally large optic disc (greater than 2.1 mm in diameter). The anomaly is usually bilateral with otherwise normal configuration of the disc, and typically associated with an increased cup-to-disc ratio, a round or horizontal oval optic cup, and an intact, pale-appearing neuroretinal rim. In a less frequent variant, a unilateral, anomalous superior excavation obliterates part of the adjacent neuroretinal rim. In general, visual acuity and visual fields are normal, except for an enlarged blind spot. Ciliary arteries are more common in megalopapilla.


A rare nervous system tumor characterized by cells phenotypically representing Schwann cells but containing melanosomes and expressing melanoma markers. The entity occurs as a non-psammomatous (typically affecting spinal nerves) or a psammomatous (also involving nerves of the intestinal tract and heart) variant. About 50% of psammomatous tumors are associated with Carney complex. Slightly over 10% of melanotic schwannomas follow a malignant course.


A rare intestinal disease characterized by isolated thrombosis of the mesenteric veins without involvement of the splenic or portal veins, potentially causing mesenteric ischemia. It may be primary/idiopathic or due to one or more local or systemic predisposing conditions, and may be acute/subacute or chronic, the latter being used for patients with symptoms lasting longer than 4 weeks but without bowel infarction, or patients without recent symptoms, where the thrombosis is an incidental finding. Symptoms depend on the extent and severity of thrombosis and often involve prolonged nonspecific abdominal complaints.


A non-syndromic group of structural developmental eye defects characterized by the variable combination of microphthalmia, ocular coloboma, and anophthalmia, either unilaterally or bilaterally, with no other associated ocular conditions in the affected/contralateral eye, and no systemic anomalies.

Summary:
Epidemiology
The prevalence of microphthalmia is 1:7,000, anophthalmia is 1:30,000 and coloboma is 1:5,000 live births, with combined prevalence 3-30:100,000 births. Associated malformations affect 32-93% of the patients. There is no clear predilection for ethnicity or gender.
Clinical description
Microphthalmia-anophthalmia-coloboma (MAC) consists of phenotypic continuum of congenital eye defects that are manifest at birth. In some cases, such as retinal coloboma or mild microphthalmia, detection may occur later in life. True anophthalmia is the abortion of eye development at the developing optic vesicle stage (3-4 weeks gestation) leading to absence of the eye, optic nerve and chiasm. Commonly clinical anophthalmia (also referred to as severe microphthalmia) occurs, where a small cystic remnant is detectable on pathology/imaging. Nanophthalmos and posterior microphthalmia, are rare subsets of microphthalmia, where overall the eye is structurally normal but it has a reduced axial length of <20 mm with high hypermetropia. Ocular coloboma may involve the inferonasal aspect of the eye, including the iris, ciliary body, zonules, retina, retinal pigment epithelium (RPE), choroid and/or optic disc.
Etiology
MAC has a complex etiology, with monogenic, chromosomal and environmental causes. SOX2, OTX2 and STRA6 variants account for 75% of bilateral anophthalmia/severe microphthalmia. Chromosomal abnormalities account for 20-30% of MAC. Environmental factors associated with anophthalmia include maternally-acquired infections, smoking and antenatal exposure to certain medications. Maternal vitamin A deficiency, alcohol abuse and use of teratogenic drugs during pregnancy have been linked to coloboma and microphthalmia.
Diagnostic methods
Postnatal diagnosis can be made through clinical examination, with confirmation of true/clinical anophthalmia through MRI brain and orbit imaging. Molecular diagnosis can be made through genetic testing, such as array comparative genomic hybridization (aCGH) or whole exome/genome sequencing.
Differential diagnosis
Differential diagnoses includes aniridia, anterior segment dysgenesis, congenital corneal opacity, sclerocornea, cryptophthalmos, cyclopia and congenital cystic eye. MAC may also occur as part of various syndromes, and thus examination by specialists for the presence of systemic features (e.g. associated neurological or pituitary defects) is recommended. Genetic diagnosis may aid the identification of potential systemic anomalies.
Antenatal diagnosis
Prenatal diagnosis of anophthalmia or microphthalmia may be made through 2D or 3D ultrasonography during the second trimester (or 12 weeks post-conception with a transvaginal ultrasound) or fetal magnetic resonance imaging to visualize the orbit.
Genetic counseling
Genetic counselling can be challenging due to the range of known genetic causes and phenotypic variability. Prediction of inheritance pattern is often difficult, due to de novo changes, mosaicism and non-penetrance. If a genetic diagnosis is established, informed family planning advice can be provided including prenatal and preimplantation diagnosis.
Management and treatment
There is no treatment for MAC patients. They should be managed by a multidisciplinary team of specialists, including ophthalmologists, pediatricians and clinical geneticists. If there is visual potential, children should be monitored to maximize vision by correcting refractive error or squints, and preventing amblyopia. Fundus examinations are required in patients with chorioretinal coloboma as it is associated with a risk of retinal detachment. Low vision should be supported using visual aids. Significant microphthalmic or anophthalmic eyes may undergo socket expansion using enlarging cosmetic shells/conformers to minimize facial deformity.
Prognosis
Isolated MAC are structural birth defects with no treatment available.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                             Philippa HARDING  - Dr Mariya MOOSAJEE


A rare disorder of the anterior segment of the eye characterized by the presence of an unusually small and spherical lens with increased anteroposterior thickness, and visibility of the lens equator on full mydriasis. The condition is typically bilateral and may be associated with lens dislocation or subluxation, lenticular myopia, and secondary angle-closure glaucoma.


Isolated congenital digital clubbing is a rare genodermatosis disorder characterized by enlargement of the terminal segments of fingers and toes with thickened nails without any other abnormality.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Isolated congenital digital clubbing is often painless and usually symmetrical and bilateral. Sometimes, some fingers or toes are spared, but the thumbs are almost always involved.
Etiology
It results from proliferation of the connective tissues between the nail matrix and the distal phalanx and abnormal function of the nail matrix. The condition can be caused by autosomal recessive mutation of the HPGD gene (4q34-q35), but autosomal dominant forms without a known genetic cause have also been reported.

                            Last update:
                            March 2010


Isolated neonatal sclerosing cholangitis is a rare, genetic, biliary tract disease characterized by severe neonatal-onset cholangiopathy with patent bile ducts and absence of ichthyosiform skin lesions. Patients present with jaundice, acholic stools, hepatosplenomegaly and high serum gamma-glutamyltransferase activity. Liver histology shows portal fibrosis, ductular proliferation, hepatocellular metallothionein deposits, and intralobular bile-pigment accumulations. Some patients may also have renal disease.


A rare inflammatory optic neuropathy characterized by isolated episodes (either single or recurrent) of optic neuritis not associated with other neurological or systemic disease. Patients typically present with subacute unilateral loss of vision progressing over several days to two weeks, periocular pain and pain on eye movement (which may precede the onset of visual symptoms), light flashes on eye movement, abnormal color vision, reduced contrast sensitivity, and relative afferent pupillary defect. The optic disc appears swollen in many patients, and uveitis may be associated and can be present for years before the onset of optic neuritis.


A rare primary bone dysplasia characterized by multiple, small, round to ovoid osteosclerotic foci with a predilection for the epiphyses and metaphyses of long tubular bones as well as the pelvis, scapula, carpal, and tarsal bones. The condition is usually clinically silent and discovered only incidentally, although some patients may experience mild articular pain with or without joint effusion. Bone strength is normal.


A rare, non-syndromic urogenital tract malformation characterized by the absence of a vagina or the presence of a vaginal dimple shorter than 5 cm. It is often associated with uterine agenesis, hematocolpos or primary amenorrhea and dyspareunia. Ovaries and fallopian tubes are normal.


Isolated patella aplasia-hypoplasia is an extremely rare genetic condition characterized by congenital absence or marked reduction of the patellar bone described in only a few families to date.


Isolated permanent neonatal diabetes mellitus

Permanent neonatal diabetes mellitus (PNDM) is a monogenic form of neonatal diabetes (NDM, see this term) characterized by persistent hyperglycemia within the first 12 months of life in general, requiring continuous insulin treatment.

Summary:
Epidemiology
The incidence of NDM is estimated to be 1/95,000 to 1/150,000 live births. About 50% of NDM cases are permanent (PNDM) and 50% transient (TNDM, see this term). The condition has been reported in all ethnic groups and affects male and female infants equally.
Clinical description
The median age of onset of PNDM is nine weeks. Initial clinical manifestations include hyperglycemia, glycosuria, intrauterine growth retardation, osmotic polyuria, severe dehydration, and failure to gain weight. The subsequent course of the disease depends on the genetic defect underlying DM. Most patients display some degree of developmental coordination disorder (including visual-spatial dyspraxia). Manifestations depend on the type of gene mutation involved. In KCNJ11 and ABCC8-related cases, patients usually present before three months of age with symptomatic hyperglycemia, and often ketoacidosis. Approximately 25% of patients with mutations in the KCNJ11 gene have associated neurological findings, including developmental delay and epilepsy (DEND syndrome, see this term) or a milder form of DEND without seizures and with less severe developmental delay (intermediate DEND, see this term). In INS-related cases, patients present with marked hyperglycemia or diabetic ketoacidosis usually at nine weeks, but some at a much later age. GCK-related PNDM patients have permanent insulin-dependent diabetes from the first day of life. Homozygous PDX1 mutations or mutations in other genes such as GATA6, PTF1A or HNF1B are related to rare cases of pancreatic hypoplasia with severe insulin deficiency and possibly exocrine pancreatic insufficiency. Two groups can be distinguished based on pancreatic involvement: patients with abnormal pancreas development and children with a normal pancreas. Long-term complications include developmental delay, microalbuminuria, and retinopathy.
Etiology
Mutations in 10 genes have been associated with PNDM: KCNJ11 (34% of cases), ABCC8 (24%), INS (13%), GCK (4%), PDX1 (<1%), GATA6, PTF1A, HNF1B, RFX6 and MNX1. These last five genes may be associated with syndromic forms. The genetic defects result in partial or complete insulin deficiency, and for the last six in possible pancreatic hypoplasia.
Diagnostic methods
Diagnosis of PNDM is made in infants under 12 months of age with persistent hyperglycemia (plasma glucose concentration >150-200 mg/dl). Molecular genetic testing of the implicated genes confirms the diagnosis and guides management.
Differential diagnosis
Differential diagnoses include type 1 diabetes mellitus, transient neonatal diabetes mellitus (TNDM), IPEX syndrome, and Wolcott-Rallison syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is available for most forms of PNDM provided that the disease-causing mutation has been identified in the family.
Genetic counseling
The pattern of inheritance is autosomal dominant or autosomal recessive depending on the gene. Genetic counseling should be provided to affected families.
Management and treatment
Immediate treatment involves rehydration and administration of intravenous insulin. Insulin can rapidly be switched to subcutaneously administered preparations. The aim is to control hyperglycemia and to enable catch-up growth. In those with KCNJ11 or ABCC8 mutations, a complete neurological assessment is recommended. Patients with activating mutations in these two genes can be treated long-term with oral sulfonylureas (currently in research protocols as no market authorization has yet been granted in this indication), and others with long-term insulin therapy.
Prognosis
Appropriate early treatment significantly reduces the risk of long-term complications.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Pr Michel POLAK