Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome

A rare genetic neurological disorder characterized by congenital microcephaly, severe intellectual disability, hypertonia at birth lessening with age, ataxia, and specific dysmorphic facial features including hirsutism, low anterior hairline and bitemporal narrowing, arched, thick, and medially sparse eyebrows, long eyelashes, lateral upper eyelids swelling and a skin fold partially covering the inferior eyelids, low-set posteriorly rotated protruding ears, anteverted nares, and a full lower lip. Brain imaging shows partial to almost complete agenesis of the corpus callosum and variable degrees of cerebellar hypoplasia.


Severe intellectual disability-epilepsy-anal anomalies-distal phalangeal hypoplasia is characterised by severe intellectual deficit, epilepsy, hypoplasia of the terminal phalanges, and an anteriorly displaced anus. It has been described in two sisters born to consanguineous parents. The syndrome is transmitted as an autosomal recessive trait and appears to be caused by anomalies in to chromosome regions, one localised to chromosome 1 and the other to chromosome 14.


Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome

A rare, genetic, syndromic intellectual disability disorder characterized by global development delay with very limited or absent speech and language, severe intellectual disability, long slender fingers, ocular abnormalities (typically strabismus or hypermetropia), and facial dysmorphism that includes a grimacing facial expression, a tubular-shaped nose with a prominent, broad base and tip, and other variable features, such as broad forehead, hypertelorism, deep-set eyes, narrow palpebral fissures, short philtrum and/or broad mouth.


Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome

A rare, genetic, syndromic intellectual disability characterized by severe intellectual disability, non-inherited, progressive, post-natal microcephaly, hypotonia, hyperkinesia, absence of speech, strabismus, and midline stereotypic hand movements (e.g. hand washing/rubbing). Additional features include developmental delay, seizures and behavioral disturbances, such as self injury and unexplained crying episodes.


Severe intellectual disability-progressive spastic diplegia syndrome

A rare, genetic, syndromic intellectual disability disorder characterized by intellectual disability, significant motor delay, severe speech impairment, early-onset truncal hypotonia with progressive distal hypertonia/spasticity, microcephaly, and behavioral anomalies (autistic features, aggression or auto-aggressive behavior, sleep disturbances). Variable facial dysmorphism includes broad nasal tip with small alae nasi, long and/or flat philtrum, thin upper lip vermillion. Visual impairment (strabismus, hyperopia, myopia) is commonly associated.


Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome

A rare, genetic, syndromic intellectual disability syndrome characterized by severe intellectual disability with limited or absent speech and language, short stature, acquired microcephaly, kyphoscoliosis or scoliosis, and behavioral disturbances that include hyperactivity, stereotypy and aggressiveness. Facial dysmorphism, that typically includes sloping forehead, mild synophrys, deep-set eyes, strabismus, anteverted large ears, prominent nose and dental malposition, is also characteristic.


Severe lateral tibial bowing-short stature-mild winged scapula-mild facial dysmorphism syndrome

Severe lateral tibial bowing with short stature is a rare, genetic, primary bent bone dysplasia characterized by significant, uni-/bilateral, lateral tibial bowing localized to the distal two-thirds of the tibia, with respective cortical thickening and thinning of the inner and outer tibial curve, loss of normal trabecular bone, bilateral abnormalities of the tibial epiphyses and growth plates, as well as foot abnormalities, including abnormally high arches. Affected individuals have short stature with absence of other skeletal abnormalities.


Severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome

A rare, multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism, including microbrachycephaly, sloping forehead, micro/anophthalmia, large ears, prominent nasal root, mild micrognathia, and cleft palate, associated with cerebral palsy with choreoathetoid movements, intellectual disability, dextrocardia and longitudinal folding of plantae pedis. There have been no further descriptions in the literature since 1992.


Severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

A rare, genetic, neurological disorder characterized by intrauterine growth retardation, failure to thrive, infantile onset of sensorineural deafness, severe global developmental delay or absent psychomotor development, paraplegia or quadriplegia with dystonia and pyramidal signs, microcephaly, ocular abnormalities (strabismus, optic atrophy), mildly dysmorphic features (deep-set eyes, prominent nasal bridge, micrognathia), seizures and abnormalities of brain morphology (hypomyelinating white matter changes, cerebral atrophy).


Severe myopia-generalized joint laxity-short stature syndrome

A rare developmental defect with connective tissue involvement characterized by joint hyperextensibility and multiple dislocations of large joints, severe myopia, and short stature. Other common features include retinal detachment, iris and chorioretinal coloboma, kyphoscoliosis and other spine deformities, pectus carinatum, talipes equinovarus, and progressive hearing loss.


Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency is a rare, hereditary, mitochondrial oxidative phosphorylation disorder characterized by severe neonatal lactic acidosis and deficiency of mitochondrial complexes I, II and III. Clinical features are variable and may include hypotonia, respiratory distress with cyanosis, failure to thrive, feeding difficulties, hypoglycemia, dehydration, vomiting, seizures, and a risk of multiple organ failure.


Severe neonatal-onset encephalopathy with microcephaly is a rare monogenic disease with epilepsy characterized by neonatal-onset encephalopathy, microcephaly, severe developmental delay or absent development, breathing abnormalities (including central hypoventilation and/or respiratory insufficiency), intractable seizures, abnormal muscle tone and involuntary movements. Early death is usual.


Severe neurodegenerative syndrome with lipodystrophy

A rare, genetic, neurodegenerative disorder characterized by progressive psychomotor and cognitive regression (manifesting with gait ataxia, spasticity, loss of language, mild to severe intellectual disability, pyramidal and extrapyramidal signs and, frequently, development of tretraplegia or tetraparesis) associated with variable degrees of lipodystrophy, hepatomegaly, hypertriglyceridemia and muscular hypertrophy. Hyperactivity, tremor and development of seizures may also be associated.


Severe neurodevelopmental disorder with feeding difficulties-stereotypic hand movement-bilateral cataract

A rare pervasive developmental disorder characterized by microcephaly, profound developmental delay, intellectual disability, bilateral cataracts, severe epilepsy including infantile spasms, hypotonia, irritability, feeding difficulties leading to failure to thrive, and stereotypic hand movements. The disease manifests in infancy. Brain imaging reveals delay in myelination and cerebral atrophy.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by profound intellectual disability, choreoathetosis, progressive spastic diplegia, progressive tapetoretinal degeneration with loss of retinal vessels, and glomerulopathy resulting in death late in the first or early in the second decade of life. Absence of the cerebellar granular layer has been reported. There have been no further descriptions in the literature since 1982.


Severe phosphoribosylpyrophosphate synthetase superactivity

A severe form of phosphoribosylpyrophosphate (PRPP) synthetase superactivity, an X-linked disorder of purine metabolism, characterized by early onset hyperuricemia and hyperuricosuria, and clinically manifesting with urolithiasis, gout and neurodevelopmental anomalies consisting of variable combinations of sensorineural hearing loss, hypotonia, and ataxia.

Summary:
Epidemiology
PRPP synthetase superactivity is a rare disorder with 30 families described in the literature. The severe form accounts for approximately 25% of cases. The disorder predominantly affects males.
Clinical description
The phenotype varies greatly among patients. The severe form manifests in infancy or early childhood (but may occur earlier) usually with uric acid crystalluria and urinary stones (kidney and/or bladder), followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. This form also shows neurologic impairment, mainly sensorineural hearing loss, hypotonia, ataxia, developmental delay, and /or intellectual disability. Axonal neuropathy with demyelination is also possible (reported in one family).
Etiology
The disease is due to overactivity of PRPP synthetase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). In the severe form, PRS-I overactivity is due to gain-of-function point mutations in the open reading frame of the PRPS1 gene (Xq22.3), encoding PRS-I, that lead to defective allosteric control of PRS1 isoform activity.
Diagnostic methods
Diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by either molecular genetic testing or a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes.
Differential diagnosis
Differential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and psychomotor delay due to S-adenosylhomocysteine hydrolase deficiency.
Antenatal diagnosis
Prenatal genetic testing in male fetuses is possible where a mutation has previously been identified in a family member.
Genetic counseling
Severe PRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance in males. A mother carrying the pathogenic mutation has a 50% chance of transmitting the mutation to any of her offspring, an affected father transmits the mutation only to his daughters. Heterozygous females are typically asymptomatic; however, symptomatic females have been reported, most likely due to X-inactivation. De novo  PRSP1 mutations have also been reported.
Management and treatment
Treatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. A high daily fluid intake is warranted; and, as needed, potassium citrate to alkalinize the urine in order to avoid the formation of kidney stones. A low-purine and low-fructose diet along with regular surveillance of serum urate concentration is essential. Regular audiometric and neurologic evaluations are also recommended.
Prognosis
The prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated. Of note, the interventions have no known beneficial effect on hearing loss or neurologic impairment.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Arjan DE BROUWER


A rare inborn error of metabolism characterized by the presence of large amounts of trimethylamine in urine, sweat, and breath, resulting in a fishy body odor in affected individuals. While there are no additional signs and symptoms, the condition can have profound psychosocial consequences.


Severe X-linked intellectual disability, Gustavson type

A rare, genetic, X-linked syndromic intellectual disability disorder characterized by severe intellectual disability, microcephaly, post-natal growth retardation, severe visual impairment or blindness (due to optic atrophy), severe hearing defect, spasticity, epileptic seizures, restricted large-joint movements and early death (in infancy or early childhood). Facial dysmorphic features (large dysplastic ears and short broad nose) are additionally observed. There have been no further descriptions in the literature since 1993.


Severe X-linked mitochondrial encephalomyopathy is an extremely rare mitochondrial respiratory chain disease resulting in a neurodegenerative disorder characterized by psychomotor delay, hypotonia, areflexia, muscle weakness and wasting in the two patients reported to date.


A group of rare tumors of testis comprising neoplasms of pure sex cord or pure stromal type, or neoplasms with admixtures of both components in various proportions and degree of differentiation. The tumors usually present as a painless testicular mass, although some may be associated with endocrine manifestations such as precocious puberty, gynecomastia, or erectile dysfunction. Malignant behavior is seen only in a small percentage of these tumors.


Sheehan syndrome is a rare, acquired, pituitary hormone deficiency disorder resulting from pituitary necrosis following peri- or postpartum hemorrhage characterized by various symptoms depending on resulting hormone decrease (e.g. failure or difficulty with lactation, oligo- or amenorrhea, hot flashes, decreased libido, weakness, fatigue, anorexia, nausea, vomiting, hypoglycemia, hyponatremia, dizziness, decreased muscle mass, adrenal crisis). Secondary hypothyroidism and secondary adrenal insufficiency may also be presenting signs.


Sheldon-Hall syndrome (SHS) is a rare multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs, triangular face, downslanting palpebral fissures, small mouth, and high arched palate.

Summary:
Epidemiology
Epidemiological data for the prevalence of SHS are not available, but less than 100 cases have been reported in the literature.
Clinical description
Other common clinical features of SHS include prominent nasolabial folds, high arched palate, attached earlobes, mild cervical webbing, short stature, severe camptodactyly, ulnar deviation, and vertical talus and/or talipes equinovarus. Typically, the contractures are most severe at birth and non-progressive.
Etiology
Mutations in either MYH3, TNNI2, or TNNT3 have been found in about 50% of cases. These genes encode proteins of the contractile apparatus of fast twitch skeletal muscle fibers.
Diagnostic methods
The diagnosis of SHS is based on clinical criteria.
Differential diagnosis
Mutation analysis is useful to distinguish SHS from arthrogryposis syndromes with similar features (e.g. distal arthrogryposis 1 and Freeman-Sheldon syndrome; see these terms).
Antenatal diagnosis
Prenatal diagnosis by ultrasonography is feasible at 18-24 weeks of gestation. If the family history is positive and the mutation is known in the family, prenatal molecular genetic diagnosis is possible.
Genetic counseling
SHS is inherited in an autosomal dominant pattern but about half the cases are sporadic.
Management and treatment
There is no specific therapy for SHS. However, patients benefit from early intervention with occupational and physical therapy, serial casting, and/or surgery.
Prognosis
Life expectancy and cognitive abilities are normal.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Pr Michaël BAMSHAD  - Dr Reha TOYDEMIR


Shiga toxin-associated hemolytic uremic syndrome

A rare thrombotic microangiopathy characterized by mechanical hemolytic anemia, thrombocytopenia, and renal dysfunction that is usually associated with prodromal enteritis caused by Shigella dysentriae type 1 or E. Coli.


Shigellosis is a bacterial infection leading to dysentery and is caused by Shigella, which are small, ubiquitous Gram-negative bacteria belonging to the enterobacteria family. There are four species: S. dysenteriae, S. flexneri, S. boydii and S. sonnei, all of which cause bacillary dysentery and are strictly limited to human hosts.

Summary:
Clinical description
Clinically, after an incubation period of 2-3 days, dysenteric syndrome appears, with 10-30 glairy, bloody watery stools per day, a high temperature (40°C) and abdominal pain. Examination of the intestinal mucosa with endoscopy shows multiple ulcerations.
Etiology
In western Europe, cases of shigellosis are either imported or limited to small familial epidemics and usually food-borne. They are mostly due to S. sonnei. The virulence of shigellas is a result of their ability to invade the intestinal epithelium by passing between contiguous epithelial cells, leading to the destruction of the intestinal mucosa.
Diagnostic methods
Diagnosis is based on evidence of the bacilli in stools.
Management and treatment
Treatment revolves around administration of antibiotics, quinolones and cotrimoxazole, and rehydration to alleviate symptoms. Strict isolation of affected individuals is essential to limit epidemics. The disease is notifiable

                            Last update:
                            August 2006

                            - Expert reviewer(s):
                            Dr Elisabeth ASLANGUL


Shone complex is a rare congenital cardiac malformation characterized by a complex of four obstructive lesions of the left heart: supravalvular mitral membrane, parachute mitral valve, muscular or membranous subvalvular aortic stenosis and coarctation of aorta. Clinical manifestations include heart murmur, shortness of breath and increased load intolerance, left ventricular hypertrophy and dilatation of the left atrium. Partial forms, involving only two or three out of the four specific anomalies, are also described and occasionally other cardiovascular anomalies (e.g. bicuspid aortic valve, patent ductus arteriosus, ventricular septal defect) may be associated.


Short bowel syndrome is an intestinal failure due to either a congenital defect, intestinal infarction or extensive surgical resection of the intestinal tract that results in a functional small intestine of less than 200cm in length and is characterized by diarrhea, nutrient malabsoption, bowel dilation and dysmobility.


Short chain acyl-CoA dehydrogenase deficiency

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a very rare inborn error of mitochondrial fatty acid oxidation characterized by variable manifestations ranging from asymptomatic individuals (in most cases) to those with failure to thrive, hypotonia, seizures, developmental delay and progressive myopathy.

Summary:
Epidemiology
Approximately 50 patients have been identified worldwide to date. The Netherlands has an estimated birth prevalence of at least 1/50,000.
Clinical description
Most infants with SCAD deficiency identified through newborn screening programs have been well at the time of diagnosis and most have remained asymptomatic. In affected individuals manifestations include seizures, developmental delay (delayed sitting/walking and/or speech/social interaction), failure to grow with poor feeding, and usually muscle weakness and hypotonia.
Etiology
Symptomatic SCAD deficiency is due to mutations in the acyl-CoA dehydrogenase, C-2 to C-3 short chain ACADS gene (12q24.31) as well as additional as yet unidentified precipitating factors.
Diagnostic methods
SCAD deficiency has been defined as the presence of (1) increased butyrylcarnitine (C4) concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions (on at least two occasions) and (2) biallelic ACADS mutations or susceptibility variants 511C>T and 625G>A. Newborn screening programs in Austria, Hungary and Iceland now usually identify patients with SCAD deficiency at birth. Asymptomatic relatives may meet the diagnostic criteria for SCAD deficiency.
Differential diagnosis
Differential diagnoses include multiple acyl-CoA dehydrogenase deficiency (MADD), ethylmalonic encephalopathy and acute ackee fruit intoxication (see these terms).
Antenatal diagnosis
Antenatal diagnosis is not relevant as asymptomatic and symptomatic family members can have the same SCAD genotype.
Genetic counseling
SCAD deficiency is inherited in an autosomal recessive manner and genetic counseling is possible.
Management and treatment
Most patients are asymptomatic and no treatment is needed. Some symptomatic patients are given riboflavin and follow a low fat/high carbohydrate diet and avoid fasting. Acute metabolic acidosis can be treated by the administration of high levels of dextrose (with or without insulin) and IV fluids. Seizures can be treated with anticonvulsants but valproate should be avoided. Pregnancies should be monitored for complications such as acute fatty liver of pregnancy and preeclampsia (see these terms). Follow-up at a metabolic clinic should include the regular assessment of growth and development and nutritional status of patients.
Prognosis
The prognosis is good in asymptomatic patients but variable in those who display the disease manifestations.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Simon OLPIN


Short fifth metacarpals-insulin resistance syndrome

A rare genetic disease characterized by the association of unilateral or bilateral short fifth metacarpals (defined as a gap of 2 mm or more between the distal end of the fifth metacarpal bone and a tangential line connecting the distal ends of the third and fourth metacarpals), insulin resistance, and spherocytosis. Familial short stature has not been reported as part of the syndrome.


A rare ciliopathy with major skeletal involvement characterized by short ribs, micromelia, limb bowing, polysyndactyly, absent ossification of the radii, tibiae and fibulae, as well as the bony elements of the hands and feet, and hypoplastic scapulae. Additional hallmarks of ciliopathic disease, such as laterality defects and cystic kidneys, have also been observed.


Short rib-polydactyly syndrome, Beemer-Langer type

A rare ciliopathy with major skeletal involvement characterized by short ribs and hypoplastic thorax, small iliac bones, short tubular bones with smooth metaphyseal margins, and bowed radii and ulnae. The tibiae are relatively well tubulated and longer than the fibulae. There is a high frequency of brain defects, while post-axial polydactyly is rare. Additional features may include cleft lip, absence of internal genitalia, and renal, biliary, and pancreatic cysts, among others.


Short rib-polydactyly syndrome, Majewski type

A rare ciliopathy with major skeletal involvement characterized by a hypoplastic thorax with short ribs and protuberant abdomen, micromelia with particularly short tibiae with ovoid configuration, pre- and postaxial polydactyly, brachydactyly, hypoplasia or aplasia of nails, and dysmorphic craniofacial features (such as prominent forehead, low-set and malformed ears, short and flat nose, lobulated tongue, micrognathia, and cleft lip/palate). Additional reported manifestations include urogenital, gastrointestinal, cardiovascular, and cerebral malformations, among others. The condition is fatal in the neonatal period.


Short rib-polydactyly syndrome, Saldino-Noonan type

A rare ciliopathy with major skeletal involvement characterized by short ribs with an extremely narrow thorax, very short limbs, absent or very small fibulae, severe metaphyseal dysplasia of tubular bones, post-axial polydactyly, and defective ossification in the calvaria, vertebrae, pelvis, and bones of the hands and feet. Congenital anomalies of multiple other organs have also been described, such as polycystic kidneys, transposition of the great vessels, and atretic lesions of the gastrointestinal and genitourinary tract. Hydrops fetalis may be observed at an early gestational age.


Short rib-polydactyly syndrome, Verma-Naumoff type

A rare ciliopathy with major skeletal involvement characterized by short ribs and extremely narrow thorax, severely shortened tubular bones with round metaphyseal ends and lateral spikes, and anomalies of multiple organs such as the heart, kidneys, liver, pancreas, intestine, and genitalia, with occasional occurrence of situs inversus totalis. Cleft lip/palate and polydactyly may also be present. The syndrome is fatal prenatally or in the perinatal period.


A group of bone malformations characterized by a narrow thorax and polydactyly (usually preaxial).

Summary:
Epidemiology
Prevalence as a group is unknown.
Clinical description
The group is heterogeneous and includes Jeune syndrome and Ellis Van Creveld syndrome (see these terms), neither of which are lethal, together with lethal chondrodysplasias: Saldino-Noonan (type 1), Majewski (type 2), Verma-Naumoff (type 3) and Beemer-Langer (Type 4; see these terms). This classification is based on radiological findings. Visceral malformations are frequent and differ between the syndromes. Some cases do not fit any category.
Etiology
Causative genes have been identified for the Ellis Van Creveld syndrome (EVC and EVC2; 4p16) and for a subset of patients with Jeune syndrome (IFT80 gene; 3q25.33).
Genetic counseling
All of these clinically different syndromes are inherited as autosomal recessive traits.

                            Last update:
                            September 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Short stature due to GHSR deficiency is a rare, genetic, endocrine growth disease, resulting from growth hormone secretagogue receptor (GHSR) deficiency, characterized by postnatal growth delay that results in short stature (less than -2 SD). The pituitary gland is typically without morphological changes, although anterior pituitary gland hypoplasia has been reported.


Short stature due to growth hormone qualitative anomaly is characterised by growth retardation and short stature (despite the presence of normal or slightly elevated levels of immunoreactive growth hormone, GH), low concentrations of insulin-like growth factor-I (IGF-I) and a significant increase in growth rate following recombinant GH therapy. Prevalence is unknown but only a few cases have been reported in the literature. The syndrome is caused by various mutations in the GH1 gene (17q22-q24) that result in structural GH anomalies and a biologically inactive molecule. Transmission is autosomal recessive.


Short stature due to partial GHR deficiency is a rare, genetic, endocrine disease characterized by idiopathic short stature due to diminished GHR function (decreased ligand binding or reduced availability of receptor), thus resulting in partial insensitivity to growth hormone.


Short stature due to primary acid-labile subunit deficiency

Short stature due to primary acid-labile subunit (ALS) deficiency is characterized by moderate postnatal growth deficit, markedly low circulating levels of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3), and hyperinsulinemia, in the absence of growth hormone (GH) deficiency or GH insensitivity.

Summary:
Epidemiology
Less than 10 cases have been reported in the literature so far.
Clinical description
Additional findings include subnormal IGF-2, IGFBP-1 and IGFBP-2 levels, as well as microcephaly, and delayed puberty and bone maturation in some cases.
Etiology
It is caused by homozygous inactivating mutations of the ALS gene (IGFALS; 16p13.3).
Genetic counseling
Primary ALS deficiency is inherited in an autosomal recessive manner.

                            Last update:
                            March 2009


A rare primary bone dysplasia characterized by severe intrauterine and postnatal growth retardation and short stature in association with craniofacial dysmorphism (such as large forehead, triangular face, low-set ears, and micro-retrognathism) and osteochondrodysplastic lesions. Radiographic findings include epiphyseal maturation delay, abnormal metaphyses, a narrow thorax, small pelvis, and short and broad metacarpal bones and phalanges. There have been no further descriptions in the literature since 1996.


Short stature-advanced bone age-early-onset osteoarthritis syndrome

A rare, primary bone dysplasia characterized by proportional short stature, early cessation of bone growth, accelerated skeletal maturation, variable presence of early-onset osteoarthritis and osteochondritis dissecans, and normal endocrine evaluation. The variable dysmorphic features include mild to relative macrocephaly, frontal bossing, midfacial hypoplasia, flat nasal bridge, brachydactyly, broad thumbs, and lordosis.


Short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by short stature, conductive hearing loss due to bilateral auditory canal atresia, mandibular hypoplasia and multiple skeletal abnormalities, including bilateral humeral hypoplasia, humeroscapular synostosis, delayed pubis rami ossification, central dislocation of the hips, and proximal femora defects, as well as bilateral talipes equinovarus, proximally implanted thumbs and lumbar hyperlordosis. Associated craniofacial dysmorphism includes micro/scaphocephaly, malar hypoplasia, high-arched palate, and simple, dysplastic pinnae with prearicular pits/tags.


Short stature-brachydactyly-obesity-global developmental delay syndrome

A rare genetic, multiple congenital anomalies syndrome characterized by short stature, hand brachydactyly with hypoplastic distal phalanges, global development delay, intellectual disability, and more variably seizures, obesity, and craniofacial dysmorphism that includes microcephaly, high forehead, flat face, hypertelorism, deep set eyes, flat nasal bridge, averted nostrils, long philtrum, thin lip vermilion, and short neck.

Summary:
Epidemiology
Less than 15 cases have been reported in the literature to date.
Clinical description
Initial presentation can be with intrauterine growth retardation or low birthweight. Symptoms of global development delay includes hypotonia, delay in achieving independent sitting and walking and marked language delay. Intellectual disability ranges from mild to severe. Ocular anomalies include strabismus, coloboma, dacryostenosis and blue sclera. Obesity develops in late infancy. Seizures can present in infancy or childhood, are phenotypically variable including absences and febrile convulsions. In addition to hypoplasia of the distal phalanges, the 4th and 5th fingers may show a marked reduction in metacarpal length; brachydactyly of the feet may also be present. Other variable features reported include bilateral absent patellae, sensorineural hearing loss, feeding difficulties in early infancy, dysphagia, kyphosis, eczema, cryptorchidism and laryngomalacia.
Etiology
The malformation is due to a loss of function in the enzyme protein arginine N-methyltransferase 7 (encoded by PRMT7, 16q22.1) resulting in decreased levels of protein arginine methylation.
Diagnostic methods
Diagnosis is based on presentation of clinical features, and can be confirmed by genetic testing.
Differential diagnosis
Differential diagnosis include Albright hereditary osteodystrophies with pseudohypoparathyroidism.
Antenatal diagnosis
There is no definitive antenatal diagnosis available, however ultrasound may show intrauterine growth retardation which should be investigated further.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Given that patients with biallelic mutations in PRMT7 present with a spectrum of multisystemic involvement, medical multidisciplinary follow-up is needed. Neurological follow up is indicated with special attention to seizures. Hearing evaluation is recommended at time of diagnosis. Surveillance should also include frequent monitoring of growth and development; regular ophthalmological follow up. Hormonal and phosphocalcic metabolism alterations have been reported in two patients so far, so this should also be tested.
Prognosis
Developmental delay and intellectual disability had been reported in all patients to date, with variable in severity. Language is more severely affected when hearing impairment is present.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Irene VALENZUELA PALAFOLL | ITHACA*

                                * European Reference Network


Short stature-craniofacial anomalies-genital hypoplasia syndrome

A rare developmental defect during embryogenesis mainly characterized by severe intellectual disability, short stature, hypogonadism, and distinct facial dysmorphism (including trigonocephaly, prominent forehead, asymmetric and flat face, hypertelorism, epicanthus, downslanting palpebral fissures, ptosis, low-set angulated ears, small mouth, high-arched/cleft palate crowded teeth, microretrognathia), as well as slender hands and/or feet. Variable additional features may include pterygia, hypoplastic nipples, cardiac anomaly, distal muscular wasting, limb contractures, skeletal anomalies (e.g. scoliosis, pectus excavatum, bilateral clubfeet), hypothyroidism, seizures, and cerebral anomalies. Puberty may be delayed.


Short stature-deafness-neutrophil dysfunction-dysmorphism syndrome

A rare developmental defect during embryogenesis malformation syndrome characterized by proportionate short stature, sensorineural deafness, mutism, facial dysmorphism and recurrent infections as a result of abnormal neutrophil chemotaxis. There have been no further descriptions in the literature since 1978.


Short stature-delayed bone age due to thyroid hormone metabolism deficiency is a rare, genetic congenital hypothyroidism disorder characterized by mild global developmental delay in childhood, short stature, delayed bone age, and abnormal thyroid and selenium levels in serum (high total and free T4 concentrations, low T3, high reverse T3, normal to high TSH, decreased selenium). Intellectual disability, primary infertility, hypotonia, muscle weakness, and impaired hearing have also been reported.


Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome

A rare, genetic, primary bone dysplasia disorder characterized by severe pre- and post-natal short stature, facial dysmorphism (incl.dolicocephaly, long triangular face, tall forehead, down-slanting palpebral fissures, prominent nose, long philtrum, small ears), early-onset or postpubertal sparse, short hair and hypoplastic fingernails. Small hands with tapering fingers, bracydactyly and fifth-finger clinodactyly, as well as a high-pitched voice are also associated.


Short stature-optic atrophy-Pelger-Huët anomaly syndrome

A rare, genetic, developmental defect during embryogenesis malformation syndrome characterized by severe postnatal growth retardation, craniofacial dysmorphism, which includes a progeroid facial appearance, brachycephaly with hypoplasia of the frontal and parietal tubers and a flat occipital area, narrow forehead, prominent glabella, small orbit, slight bilateral exophthalmos, straight nose, hypoplastic cheekbones, long philtrum and thin lips, skeletal abnormalities (i.e. micromelia, brachydactyly, and severe short stature with short limbs), normal intelligence, Pelger-Huët anomaly of leukocytes, loose skin with decreased tissue turgor, and bilateral optic atrophy with loss of color vision and visual acuity. Recurrent liver failure triggered by fever has been occasionally reported. Radiographs may evidence delayed bone age, late ossification and/or osteoporosis.


Short stature-pituitary and cerebellar defects-small sella turcica syndrome is characterised by short stature, anterior pituitary hormone deficiency, small sella turcica, and a hypoplastic anterior hypophysis associated with pointed cerebellar tonsils. It has been described in three generations of a large French kindred. Ectopia of the posterior hypophysis was observed in some patients. The syndrome is transmitted as a dominantly inherited trait and is caused by a germline mutation within the LIM-homeobox transcription factor LHX4 gene (1q25).


Short stature-skeletal dysplasia-retinal degeneration-intellectual disability-sensorineural hearing loss syndrome

A rare primary bone dysplasia characterized by microcephaly, developmental delay and intellectual disability, sensorineural hearing loss, retinal degeneration, and skeletal dysplasia. Musculoskeletal abnormalities include delayed ossification of epiphyses, spondyloepimetaphyseal dysplasia, short stature, severe spinal deformities, and severe joint laxity resulting in multiple joint dislocations.


Short stature-valvular heart disease-characteristic facies syndrome is characterised by severe short stature with disproportionately short legs, small hands, clinodactyly, valvular heart disease and dysmorphism (ptosis, high-arched palate, abnormal dentition). It has been described in a mother and two daughters. This syndrome is probably transmitted as an autosomal dominant trait.


Short stature-webbed neck-heart disease syndrome is characterized by short stature, intellectual deficit, facial dysmorphism, short webbed neck, skin changes and congenital heart defects. It has been reported in four Arab Bedouin sibs born to consanguineous parents.


Short stature-wormian bones-dextrocardia syndrome

A multiple congenital anomalies syndrome characterized by wormian bones, dextrocardia and short stature due to a growth hormone deficiency. Additional manifestations that have been reported include brachycamptodactyly, kidney hypoplasia, bilateral cryptorchidism, midshaft hypospadias, imperforate anus/anorectal agenesis, body asymmetry, mild developmental delay, hemimegalencephaly and facial dysmorphism (hypotelorism, downslanting palpebral fissures, low-set and posteriorly angulated ears, depressed nasal bridge, and microstomia).


A rare disorder characterized by multiple congenital anomalies. The name is a mneumonic for the common features observed in SHORT syndrome that include; short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay. Other common manifestations of SHORT syndrome are mild intrauterine growth restriction, partial lipodystrophy, delayed bone age, hernias and a recognizable facial gestalt.

Summary:
Epidemiology
The prevalence of SHORT syndrome is unknown. Less than 50 cases have been reported in the literature to date.
Clinical description
Individuals with SHORT syndrome often display mild intrauterine growth restriction. Feeding difficulties and/or failure to thrive present in early childhood and final adult height is shorter than average (155-163 cm in males and 143-160 cm in females). Most patients have a characteristic facial gestalt, often described as progeroid, with triangular face shape, prominent forehead, ocular depression, hypoplastic alae nasi, low-hanging columella, downturned corners of the mouth, micrognathia and prominent (but not typically low-set or posteriorly located) ears. Partial lipodystrophy may be evident in the face at birth and later in the chest and upper extremities (including the hands), but it is usually not reported in the buttocks and legs. Delayed dentition, hypodontia, enamel hypoplasia, malocclusion and multiple dental caries are frequently reported. Ophthalmic anomalies (e.g. Rieger anomaly, Axenfeld anomaly (see these terms), glaucoma) are also characteristic of the disease. Diabetes is seen in approximately 2/3 of individuals with SHORT syndrome after the age of 15 years. Other less common manifestations include hyperextensibility of joints and/or hernias, sensorineural hearing loss and ovarian cysts in females. Intellectual development and cognition are usually unaffected although mild impairment with speech delay has been reported.
Etiology
SHORT syndrome is due to mutations in the PIK3R1 gene (5q13.1), encoding phosphatidylinositol 3-kinase regulatory subunit alpha. Mutations are thought to impair the PI3K/AKT/mTOR pathway, which plays an important role in cellular proliferation and growth.
Diagnostic methods
Diagnosis is based on the presence of the characteristic features and confirmed by molecular genetic testing identifying a PIK3R1 mutation. The presence of all 5 features of the acronym is not necessary for a positive diagnosis.
Differential diagnosis
Differential diagnoses include Silver-Russell syndrome, Alagille syndrome, Floating-Harbor syndrome, growth delay due to insulin-like growth factor I resistance, Berardinelli-Seip congenital lipodystrophy and Hutchinson-Gilford progeria syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
SHORT syndrome is inherited in an autosomal dominant manner. Genetic counseling is recommended for at-risk families. De novo cases have also been described. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Treatment is symptomatic and requires a multidisciplinary team. Screening for insulin resistance is recommended starting in mid-late childhood. Glucose intolerance and diabetes mellitus can be treated with diet, lifestyle, oral medication and insulin, while growth hormone therapy is contraindicated. Ophthalmological management and follow-up (i.e. regular eye examinations) are necessary to reduce and stabilize ocular pressures and to preserve vision. Dental anomalies can be treated using standard methods (e.g. crowns and dental prostheses).
Prognosis
Individuals with SHORT syndrome are considered to have a normal life-expectancy.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr David DYMENT  - Dr A.Micheil INNES


Short tarsus-absence of lower eyelashes syndrome

Short tarsus - absence of lower eyelashes is a very rare syndrome characterized by the association of thin and short upper and lower tarsus and absence of the lower eyelashes.

Summary:
Epidemiology
It has been described in 11 patients from a four generation family.
Clinical description
There is no other unusual feature.
Genetic counseling
Inheritance is autosomal dominant.

                            Last update:
                            October 2010


Short ulna-dysmorphism-hypotonia-intellectual disability syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by mild to severe global development delay, severe intellectual disability, mild hypotonia, a short ulna, hirsutism of the face and extremities, minimal scoliosis, and facial dysmorphism, notably a tall broad forehead, synophrys, hypertelorism, malar hypoplasia, broad nose with thick alae nasi, low-set, small ears, long philtrum, thin upper lip and everted lower lip vermilion.


Short-limb skeletal dysplasia with severe combined immunodeficiency

An extremely rare type of severe combined immunodeficiency (SCID) characterized by the classical signs of T-B- SCID (severe and recurrent infections, diarrhea, failure to thrive, absence of T and B lymphocytes), associated with skeletal anomalies like short stature, bowing of the long bones and metaphyseal abnormalities of variable degree of severity.


SHOX-related short stature is a primary bone dysplasia characterized by a height that is 2 standard deviations below the corresponding mean height for a given age, sex and population group, in the absence of obvious skeletal abnormalities and other diseases and with normal developmental milestones. Patients present normal bone age with normal limbs, shortening of the extremities (significantly lower extremities-trunk and sitting height-to-height ratios), normal hGH values, normal karyotype, and Leri-Weill dyschondrosteosis-like radiological signs (e.g. triangularization of distal radial epiphyses, pyramidalization of distal carpal row, and lucency of the distal radius on the ulnar side). Mesomelic disproportions and Madelung deformity are not apparent at a young age, but may develop later in life or never.


A rare genetic disorder characterized by craniosynostosis, craniofacial and skeletal abnormalities, marfanoid habitus, cardiac anomalies, neurological abnormalities, and intellectual disability.


Shwachman-Diamond syndrome (SDS) is a rare multisystemic syndrome characterized by chronic and usually mild neutropenia, pancreatic exocrine insufficiency associated with steatorrhea and growth failure, skeletal dysplasia with short stature, and an increased risk of bone marrow aplasia or leukemic transformation.

Summary:
Epidemiology
Worldwide prevalence is estimated at about 1/350,000 and birth-prevalence at around 1/200,000 live births.
Clinical description
SDS shows a variable clinical picture, even within families. It generally manifests during infancy or early childhood. The most common anomaly is usually intermittent and moderate neutropenia that is associated with recurrent infections. Mild anemia and thrombocytopenia may also occur. Exocrine pancreatic insufficiency results in failure to thrive, growth retardation, and chronic steatorrhea. Bone involvement is characterized by delayed bone age and maturation with metaphyseal dysplasia resulting in short stature, pectus carinatum, and generalized osteopenia. Other features include cutaneous (e.g. eczema or ichthyosis) and dental anomalies, and psychomotor retardation. Mild or severe intellectual disability (50% of patients) causes learning difficulties. Hematologic manifestations may be complicated by bone marrow aplasia, acute myeloid leukemia or a myelodysplastic syndrome (see these terms). In the neonatal period there are generally no symptoms observed but some cases were reported with pancytopenia, respiratory distress, and severe spondylometaphyseal dysplasia (see this term).
Etiology
SDS is caused in 95% of cases by mutations in the SBDS gene (7q11.22) encoding a ribosomal protein involved in ribosomal biogenesis and other cellular processes.
Diagnostic methods
Diagnosis is based on clinical, laboratory, and radiologic findings. Blood analysis shows neutropenia (absolute neutrophil count <1500/mL) that can be associated with mild to moderate thrombocytopenia, moderate anemia, and a rise in fetal hemoglobin. Exocrine pancreatic insufficiency can be detected by serum analysis showing low levels of pancreatic isoamylase and/or trypsinogen, stool analysis showing low fecal elastase, and magnetic resonance imaging (MRI) revealing a characteristic pancreatic aspect with fat degeneration (MRI could be normal until the age of 5). Imagery also allows detection, usually after the age of 5, of metaphyseal anomalies and abnormal growth plate development. Bone marrow smears usually reveal varying degrees of hypocellularity with dysgranulopoieisis or dyserythropoieisis. Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnoses include cystic fibrosis, Pearson syndrome, Fanconi anemia, Johanson-Blizzard syndrome, Blackfan-Diamond anemia, celiac disease, and autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (see these terms).
Antenatal diagnosis
Prenatal diagnosis is feasible in families in which the disease-causing mutation has already been identified.
Genetic counseling
Transmission is autosomal recessive. Recurrence risk is of 25%.
Management and treatment
Management is multidisciplinary, associating usually a hematologist, a gastroenterologist and other specialists such as a nutritionist, endocrinologist, or orthopedist. Pancreatic insufficiency requires pancreatic enzyme supplementation, adapted to the diet. Antibiotic therapy prophylaxis may be sufficient to avoid infections; otherwise, granulocyte colony-stimulating factor can be proposed. Severe hematological complications require hematopoietic stem cell transplantation. Surgery may be proposed for skeletal anomalies. Patients with learning difficulties require specific educational support.
Prognosis
Prognosis is variable. Life-threatening complications include bone marrow aplasia and leukemic transformation, and occasionally viral infections. About 1/3 of patients present such complications, and some can be treated successfully by bone marrow transplant.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Jean DONADIEU


Sialidosis type 1 (ST-1) is a very rare lysosomal storage disease, and is the normosomatic form of sialidosis (see this term), characterized by gait abnormalities, progressive visual loss, bilateral macular cherry red spots and myoclonic epilepsy and ataxia, that usually presents in the second to third decade of life.

Summary:
Epidemiology
The prevalence of ST-1 is unknown but it is less frequent than sialidosis type 2 (ST-2, see this term). The prevalence of sialidosis (types 1 and 2 combined) has been estimated at approximately 1/5,000,000-1/1,500,000 live births.
Clinical description
The disease usually presents in adolescence (onset usually between 12 and 25 years) with gait disturbance, walking difficulties and/or a loss of visual acuity. Almost all patients display a cherry-red spot on the retina. They may also have generalized myoclonus, in some cases associated with seizures and ataxia. Color vision progressively diminishes while night blindness appears and, in some cases, corneal opacities and nystagmus are present. Intellectual capacity is normal. In contrast to ST-2, patients do not show facial dysmorphism, bone dysplasia or psychomotor retardation.
Etiology
ST-1 is due to a mutation of the N-acetyl-alpha-neuraminidase-1 (NEU1) gene (6p21) encoding the lysosomal enzyme neuraminidase, that initiates the degradation of sialoglycoconjugates in lysosomes. Mutations lead to a decrease in enzyme activity and consequently to an accumulation of sialyloligosaccharides in tissues. Disease severity is linked to level of residual neuraminidase activity in vivo and varies between patients.
Diagnostic methods
An ophthalmological examination (fundoscopy) can visualize bilateral cherry-red spots. Magnetic resonance imaging of the brain can reveal diffuse brain atrophy in advanced cases, but is usually normal on first examination. Detection of urinary sialyloligosaccharides can be suggestive of a diagnosis, but excretion levels may be quite low. The diagnosis must be confirmed by the demonstration of deficient neuraminidase activity (in the presence of normal beta-galactosidase activity) in leukocytes or, preferably, in cultured fibroblasts. Diagnosis can be confirmed by molecular genetic testing revealing mutations in the NEU1 gene.
Differential diagnosis
The main differential diagnosis is galactosialidosis (see this term), which is characterized by deficiencies in both neuraminidase and beta-galactosidase.
Antenatal diagnosis
Prenatal diagnosis can be performed by enzyme activity measurement or by molecular genetic analysis if the underlying molecular defect in the family is well established.
Genetic counseling
ST-1 is inherited in an autosomal recessive manner. Genetic counseling is possible.
Management and treatment
There is no cure for ST-1 and management should be multidisciplinary to allow for adapted symptomatic treatment, which is essential for improving the quality of life of affected patients. In severe cases, patients may require the use of a wheelchair.
Prognosis
There appears to be no major effect on life expectancy but quality of life can be affected due to myoclonus and resulting mobility issues.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                            Dr Roseline FROISSART  - Dr Nathalie GUFFON-FOUILHOUX


Sialidosis type 2 (ST-2) is a rare lysosomal storage disease, and the severe, early onset form of sialidosis (see this term) characterized by a progressively severe mucopolysaccharidosis-like phenotype (coarse facies, dysostosis multiplex, hepatosplenomegaly), macular cherry-red spots as well as psychomotor and developmental delay. ST-2 displays a broad spectrum of clinical severity with antenatal/congenital, infantile and juvenile presentations.

Summary:
Epidemiology
The prevalence of ST-2 is unknown. The prevalence of sialidosis (types 1 and 2 combined) has been estimated at approximately 1/5,000,000-1/1,500,000 live births.
Clinical description
ST-2 has a wide range of clinical manifestations and is usually divided into congenital/antenatal, infantile and juvenile forms. The congenital/antenatal form is characterized by non-immune hydrops fetalis, or ascites, presenting in utero or at birth and by the development of a mucopolysaccharidosis (see this term)-like phenotype including coarse facial features, dysostosis multiplex, hepatosplenomegaly, and umbilical and inguinal hernias. Surviving children and patients with the infantile onset form (before 12 months of age) are characterized by a mucopolysaccharidosis-like phenotype that includes coarse facies, dysosotosis multiplex, kyphosis, short stature (with a slowing of growth towards 18 months of age), hepatosplenomegaly, hearing impairment, cherry-red spot on the retina (a constant feature after 3 years of age), corneal opacities (rarely) and speech and developmental delay, followed by psychomotor regression and myoclonus and ataxia in some cases. Renal disease (nephrosialidosis) has been reported in some patients. The juvenile form usually presents after the age of 2 with less pronounced coarse facies, angiokeratoma, myoclonic seizures, macular cherry red spots, and psychomotor regression.
Etiology
ST-2 is due to a mutation of the N-acetyl-alpha-neuraminidase-1 (NEU1) gene (6p21) encoding the lysosomal enzyme neuraminidase, that initiates the degradation of sialoglycoconjugates in lysosomes. Mutations lead to a deficiency in enzyme activity and consequently to an accumulation of sialyloligosaccharides in tissues. In general, a higher residual neuraminidase activity is associated with milder symptoms and a longer lifespan.
Diagnostic methods
An ophthalmological examination (fundoscopy) can visualize the bilateral macular cherry-red spots. Neuroimaging shows varying degrees of brain and cerebellar atrophy. The diagnosis is suspected by detection of urinary sialyloligosaccharide excretion and must be confirmed by demonstration of the neuraminidase enzyme deficiency (in the presence of normal beta-galactosidase activity) in leukocytes or, preferably, in cultured fibroblasts. Molecular genetic testing revealing causal mutation(s) can also confirm the diagnosis. The presence of echographic signs (such as hydrops, edema, ascites) may aid in diagnosing antenatal forms during pregnancy.
Differential diagnosis
The main differential diagnoses include galactosialidosis (characterized by deficiencies in both beta galactosidase and neuraminidase) and mucopolysaccharidosis type 1, 2 or 6 (see these terms). Many patients of the juvenile sub-group, in particular, may appear to have a form of galactosialidosis.
Antenatal diagnosis
Prenatal diagnosis can be performed by measurement of enzyme activity or by molecular genetic analysis if the underlying molecular defect in the family is well established
Genetic counseling
ST-2 is inherited in an autosomal recessive manner. Genetic counseling is possible.
Management and treatment
There is no cure for ST-2 and management is multidisciplinary involving mainly palliative care. Anti-convulsants may be used to treat myoclonic seizures, but are only rarely effective. Hematopoietic stem cell transplantation has not been successful in preventing psychomotor regression, bone changes or nephrosialidosis.
Prognosis
The prognosis depends on the form of ST-2. The congenital form leads to still-birth or death within the first two years of life. For the other forms, life expectancy does not generally exceed two decades.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                            Dr Roseline FROISSART  - Dr Nathalie GUFFON-FOUILHOUX


Sialidosis is a lysosomal storage disease, belonging to the group of oligosaccharidoses or glycoproteinoses, with a wide clinical spectrum that is divided into two main clinical subtypes: sialidosis type I (see this term), the milder, non dysmorphic form of the disease characterized by gait abnormalities, progressive visual loss, bilateral macular cherry red spots and myoclonus, that presents in adolescence or adulthood (second or third decade of life); and sialidosis type II (see this term) the more severe, early onset form, characterized by a progressive and severe mucopolysaccharidosis-like phenotype with coarse facies, visceromegaly, dysostosis multiplex, and developmental delay. Bilateral macular cherry red spots are also present. Sialidosis type II has been further divided into congenital (with hydrops fetalis), infantile and juvenile presentations.


An extremely rare metabolic disorder described in fewer than 10 patients to date and characterized by variable signs and symptoms, mostly in infancy, including transient failure to thrive, slightly prolonged neonatal jaundice, equivocal or mild hepatomegaly, microcytic anemia, frequent upper respiratory infections, gastroenteritis, dehydration and flat and coarse facies. Learning difficulties and seizures may occur in childhood.


A severe form of sickle cell disease (SCD) characterized by homozygosity for the sickle hemoglobin (HbS) gene and which acutely manifests with severe anemia, susceptibility to severe bacterial infections, and ischemic vasoocclusive accidents (VOA). It is a red cell disease of genetic origin which manifests with hemolytic disease and loss of red cell deformability leading to other occlusive events.

Summary:
Epidemiology
Sickle cell anemia (SCA) is the most common form of SCD. Worldwide, it is estimated that there are over 400,000 newborns with sickle cell anemia. The birth prevalence varies according to region, with prevalence greatest in regions affected by holoendemic malaria. In Europe, the pooled birth prevalence is 1/2,300, although this varies between countries.
Clinical description
The disease does not manifest during fetal life or up to the first three months of life due to the presence of high levels of fetal hemoglobin. Clinical manifestations evolve with age and are extremely variable between individuals and at different times. In addition to anemia and bacterial infections, VOAs cause hyperalgic focal ischemia (and sometimes infarction) when they occur in the abdomen, chest or skeleton. Over the course of time, VOAs may compromise the integrity of tissues or organs.
Etiology
SCA is due to homozygous mutations (rs334) in the beta globin gene, HBB (11p15.4); this variant is termed HbS. There are other forms of sickle cell disease are due to compound heterozygosity for the HbS gene and other hemoglobin (Hb) variants. Under deoxygenated conditions, HbS polymerizes and thereby alters the shape and function of erythrocytes, triggering a cascade of events that leads to hemolysis, vascular occlusion, reduced bioavailability of nitric oxide, and endothelial injury.
Diagnostic methods
Diagnosis is based on analysis of hemoglobin using isoelectric focusing or capillary electrophoresis combined with HPLC, solubility test (Itano test) and molecular analysis. Screening of healthy carriers, by family or by population surveys, helps prevention but requires prospective genetic counseling.
Differential diagnosis
Differential diagnoses include other hereditary hemolytic diseases, and those with recurrent vascular obstruction.
Antenatal diagnosis
Following genetic counseling, prenatal genetic diagnosis is possible via chorionic villi sampling (before 14 weeks of amenorrhea) or amniotic fluid (from 17 weeks onwards).
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
From birth, management should integrate prevention of infections, pain and eventual complications, with social, psycho-educational and nutritional support, within multidisciplinary centers that are equipped with intensive care (immediate access to blood transfusion). Special attention should be paid to pregnant women with SCA. Prospective research of vasculopathies is needed. An orphan drug based on hydroxycarbamide (hydroxyurea) has obtained European marketing authorization for the severe forms of the disease. Regular or occasional transfusions remain an essential therapeutic method. Bone marrow transplantation has its main indication in severe cases, particularly in cases with cerebral vasculopathy. L-glutamine, crizanlizumab and voxelotor are currently in phase III trials.
Prognosis
The prognosis is difficult to predict. Acute bacterial infections, malarial attacks, splenic sequestration, severe VOA or organ failure can be a cause of death.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr Frédéric GALACTEROS | EuroBloodNet*

                                * European Reference Network


Sickle cell-beta-thalassemia disease syndrome

A rare, genetic hemoglobinopathy that affects red blood cells both in the production of abnormal hemoglobin, as well as the decreased synthesis of beta globin chains. Clinical manifestations depend on the amount of residual beta globin chains production, and are similar to sickle cell disease, including anemia, vascular occlusion and its complications, acute episodes of pain, acute chest syndrome, pulmonary hypertension, sepsis, ischemic brain injury, splenic sequestration crisis and splenomegaly.


Sickle cell-hemoglobin C disease syndrome

A rare, genetic hemoglobinopathy characterized by anemia, reticulocytosis and erythrocyte abnormalities including target cells, irreversibly sickled cells and crystal-containing cells. Clinical course is similar to sickle cell disease, but less severe and with less complications. Signs and symptoms may include acute episodes of pain, splenic infarction and splenic sequestration crisis, acute chest syndrome, focal segmental glomerulosclerosis, ischemic brain injury, peripheral retinopathy, and osteonecrosis.


Sickle cell-hemoglobin D disease syndrome

A rare, genetic hemoglobinopathy characterized by all the characteristics of sickle cell anemia (SCA). Clinical course is similar to SCA, including acute episodes of pain, splenic infarction and splenic sequestration crisis, vaso-occlusive crisis, acute chest syndrome, ischemic brain injury, osteomyelitis and avascular bone necrosis. The genotype is characterized by an HbS allele in combination with the HbD variant, beta121Glu>Gln.


Sickle cell-hemoglobin E disease syndrome

A rare, genetic hemoglobinopathy usually characterized by mild microcytic hemolysis and, very rarely, vaso-occlusive complications. Severe manifestations have been reported, including hematuria, splenic infarction, acute chest syndrome, acute episodes of pain and reversible bone marrow necrosis. The genotype is characterized by an HbS allele in combination with an HbE variant (beta26glu>lys); symptoms are due to the low allelic expression of HbE leading to HbS predominance (65+/-5%).


Sideroblastic anemias (SA) are a group of rare heterogeneous inherited or acquired bone marrow disorders, isolated or part of a syndrome, characterized by decreased hemoglobin synthesis, because of defective use of iron (although plasmatic iron levels may be normal or elevated) and the presence of ringed sideroblasts in the bone marrow due to the pathologic iron overload in mitochondria as visualized by Perls' staining. The group encompasses (idiopathic) acquired sideroblastic anemia and constitutional sideroblastic anemias (see these terms). The latter include syndromic sideroblastic anemias such as Pearson syndrome, mitochondrial mypathy and sideroblastic anemias, x-linked sideroblastic anemia-ataxia, thiamine responsive megaloblastic anemia syndrome and nonsyndromic sideroblastic anemias comprising x-linked and autosomal recessive sideroblastic anemias (see these terms).


A rare, syndromic, genetic respiratory disease characterized by cataracts, otitis media, intestinal malabsorption, chronic respiratory infections, and failure to thrive. Recurrent pneumonia and progressive azotemia, leading to end-stage renal disease and early death, are additionally observed. There have been no further descriptions in the literature since 1992.


A rare otorhinolaryngologic disease characterized by adult-onset progressive enophthalmos due to collapse of some or all of the maxillary sinus walls and remodeling of the orbital floor.

Summary:
Epidemiology
Its prevalence is unknown but around 550 cases have been reported in the literature so far. Patients typically present at 30-60 years old, with no sex predilection.
Clinical description
The progressive enophthalmos may occasionally be associated with hypoglobus, diplopia, headache, and facial pressure/pain. Patients sometimes report a history of remote episodes of sinusitis. The syndrome may be idiopathic or occur following a bony orbital decompression resulting from Graves' ophthalmopathy or orbital floor fracture.
Etiology
The underlying mechanism involves obstruction of the ostiomeatal complex followed by development of hypoventilation and negative maxillary sinus pressure. This negative pressure subsequently collapses the sinus and causes inward bowing of the ipsilateral orbital floor.
Diagnostic methods
Diagnosis is made by facial computerized tomography (CT) scanning with coronal reconstructions, showing a collapse of the maxillary sinus wall(s) and opacification of the sinus cavity. The ostium of the maxillary sinus is occluded due to lateral retraction of the uncinate process and apposition against the inferomedial orbital wall. The middle meatus is enlarged.
Differential diagnosis
Differential diagnosis should include orbital floor 'blow-out' fractures, soft tissue atrophy, primary or secondary malignancy, orbital venous malformations, bone growth arrest following radiation therapy, congenital etiologies (minor forms of hemifacial microsomia, plagiocephaly, microphthalmos etc.) and pseudoenophthalmos (unilateral blepharoptosis, Horner syndrome, contralateral exophthalmos, contralateral high myopia and contralateral eyelid retraction).
Management and treatment
Surgery is the only treatment. Functional endoscopic sinus surgery (FESS) is performed to open the ostiomeatal complex, with complete uncinectomy, and prevent development of negative maxillary pressure. Residual ophthalmic symptoms (e.g., enophthalmos) may be addressed by reconstructing the orbital floor in conjunction or in discontinuity with FESS.
Prognosis
Improvement in clinical symptoms, including enophthalmos and hypoglobus, is seen in a majority of patients.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                             Abiri ARASH  - Dr Edward KUAN


A rare genetic syndrome with limb malformations as a major feature characterized by brachydactyly and distal symphalangism, pes cavus, scoliosis, and normal stature. There have been no further descriptions in the literature since 1978.


Silver-Russell syndrome due to maternal uniparental disomy of chromosome 7 is a genetic malformation syndrome with short stature characterized by severe prenatal and postnatal growth retardation, feeding difficulties, body asymmetry, dysmorphic craniofacial features (triangular-shaped face, relative macrocephaly, frontal bossing, micrognathia, down-turned corners of the mouth) and other anomalies (fifth finger clinodactyly, café au lait macules, male genital anomalies, mild developmental delay and/or speech delay with movement disorders).


Silver-Russell syndrome is characterized by growth retardation with antenatal onset, characteristic facies and limb asymmetry.

Summary:
Epidemiology
The incidence is evaluated at 1-30/100 000 cases and about 400 cases have been reported in the literature.
Clinical description
Weight is often more affected than size, with little subcutaneous fat tissue. Bone maturation is delayed, in accordance with small stature. The fontanelle may be late to close. The skull has a normal circumference, which may contrast with the rest of the body and confers a pseudohydrocephalic appearance. The wide prominent forehead contrasts with the small, triangular face with a small pointed chin, a wide mouth with thin lips and down-turned corners, large eyes and bluish sclera. Lateral and usually partial asymmetry of the limbs is observed in 60% to 80% of cases, but is not progressive. Shortness and/or clinodactyly of the fifth fingers is a common finding. Patients may be slow to learn motor skills, and in rare cases, may be mildly intellectually deficient.
Etiology
Etiology is heterogeneous. Most cases are sporadic. Maternal uniparental disomy of chromosome 7 is observed in 10% of patients. Approximately 30% of the cases show hypomethylation of the H19 gene, located in the 11p15 imprinted region. Hypomethylation results in most cases from an epigenetic mechanism or a genomic microrearrangement, such as a maternal microduplication of the region.
Diagnostic methods
Diagnosis is mainly clinical, as there is no specific biological test, but it can be confirmed by the detection of the underlying molecular anomaly.
Differential diagnosis
Differential diagnosis includes intrauterine growth retardation due to impaired placental function, structural or mosaic chromosomal abnormalities, neonatal progeria (Wiedemann-Rautenstrauch syndrome), 3M syndrome and Mulibrey dwarfism (see these terms). Genetic counselling depends on the molecular mechanism involved.
Antenatal diagnosis
Prenatal diagnosis is not usually possible (as most cases reported so far are sporadic, the potential risk of having an affected child is not anticipated during pregnancy).
Genetic counseling
The recurrence risk is extremely low in cases of uniparental disomy of chromosome 7 or epigenetic anomalies of the 11p15 region.
Management and treatment
Treatment is supportive. Growth hormone therapy can speed up the growth and increases the final height, but does not allow the target height to be reached.
Prognosis
Beyond short stature and slender build, long-term prognosis is good. Hemihypotrophy is not associated with an increased tumoral risk.

                            Last update:
                            September 2007

                            - Expert reviewer(s):
                            Pr Annick TOUTAIN


A rare Prader-Willi-like syndrome characterized by severe obesity due to SIM1 mutation, in addition to some clinical features of Prader-Willi- syndrome including intellectual disability, developmental delay, behaviour problems and facial dysmorphism. Unlike Prader-Willi syndrome, short stature, hypotonia and hypogonadism may not be observed.


Simple (monoclonal) cryoglobulinemia or type I cryoglobulinemia refers to the presence in the serum of one isotype or subclass of immunoglobulin (Ig) that precipitates reversibly below 37°C.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
This serological disorder is almost invariably associated with well-known hematological disorders, usually B-cell dyscrasias (multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia; see these terms). Type I cryoglobulinemia is frequently asymptomatic per se but patients may develop acrocyanosis, retinal hemorrhage, Raynaud's phenomenon, and arterial thrombosis. These symptoms may be the expression of hyperviscosity syndrome due to high levels of monoclonal cryoglobulins. The cryoprecipitate in type I cryoglobulinemia is usually composed of IgG or IgM, but infrequent cases with IgA and very rarely monoclonal light-chain protein cryoprecipitation have been reported. Type I cryoglobulins lack rheumatoid factor activity (RF) and do not easily activate complement.
Etiology
The pathogenetic processes in simple cryoglobulinemia generally appear to be related to those of the underlying lymphoproliferative diseases. The mechanisms of cryoprecipitation are poorly understood but may be partially related to the structure of the component immunoglobulin heavy and light chains.
Diagnostic methods
Diagnosis is based on detection of cryoglobulins through blood sampling, clotting, and serum separation (carried out at 37°C), and cryoglobulin isolation and cryocrit determination (carried out at 4°C). Ig composition is commonly evaluated by simple diffusion on agarose gels or by immunoelectrophoresis (performed at 37°C to avoid precipitation and loss of cryoglobulins during the procedures).
Differential diagnosis
The principle differential diagnosis is mixed cryoglobulinemia (MC type II-III; see these terms). Type I cryoglobulinemia and MC type II-III are two distinct clinico-serological entities. In contrast to type I cryoglobulinemia, the cryoprecipitate in MC type II-III is composed ofimmune complexes containing polyclonal IgGs and mono- (type II) or polyclonal (type III) IgMs. Patients with simple cryoglobulinemia lack the typical vasculitic manifestations and serological findings (RF positivity and low complement C4) that characterize MC patients. Clinical course, treatment, and prognosis of type I cryoglobulinemia largely depend on the underlying disorder. Patients with a benign monoclonal gammopathy of undetermined significance are generally asymptomatic or present with a mild disorder.
Management and treatment
Plasma exchange treatment, with/without steroids and/or immunosuppressors, is beneficial for simple cryoglobulinemia patients presenting with clinically overt hyperviscosity syndrome. In patients with malignant B-cell neoplasias, the chemotherapy may lead to resolution of this serological manifestation.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Pr Clodoveo FERRI


A rare X-linked multiple congenital anomalies syndrome characterized by pre- and postnatal overgrowth, distinctive craniofacial features, variable congenital malformations, organomegaly and an increased tumor risk.

Summary:
Epidemiology
The birth prevalence is unknown. Approximately 250 cases have been reported to date.
Clinical description
Simpson-Golabi-Behmel syndrome (SGBS) manifests a broad clinical picture with varying degrees of severity. It is characterized by pre- and postnatal overgrowth with macrosomia, distinctive craniofacial features (macrocephaly with coarse face, macroglossia, hypertelorism, dental malocclusion, palatal abnormalities), supernumerary nipples, congenital heart defects and arrhythmias, vertebral segmental defects, abdominal visceromegaly (renal dysplasia/nephromegaly, splenomegaly and hepatomegaly), diaphragmatic hernia, diastasis recti/umbilical hernia, limb anomalies (polydactyly/brachydactyly of the hands, cutaneous syndactyly, nail hypoplasia), and genital involvement (cryptorchidism, hypospadias). Involvement of central nervous system presents with variable degrees of intellectual disability, motor delay and speech delay. Patients with SGBS are at increased risk for embryonal tumors (Wilms tumor), hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma.
Etiology
SGBS is due to loss-of-function mutations in the GPC3 gene (Xq26), encoding Glypican-3 (GPC3), a cell surface heparin sulfate proteoglycan which acts as a negative regulator of Hedgehog (Hh) signaling during development. Mutations in GPC3 result in the hyperactivation of Hh signaling, that ultimately leads to overgrowth and cancer.
Diagnostic methods
Diagnosis is based on clinical findings, family history, genetic testing for GPC3 mutations, and array comparative genomic hybridization (aCGH) analysis of genomic imbalance in Xq26. Imaging techniques help to detect skeletal anomalies and central nervous system involvement. Screening for embryonic tumors is performed by imaging (serial abdominal ultrasonogram and chest X rays), serial measurement of tumor markers and catecholamine metabolites in urine. Kidney function is monitored in cases of kidney involvement.
Differential diagnosis
Differential diagnosis include overgrowth syndromes such as Beckwith-Wiedemann syndrome and Sotos syndrome, and additional disorders such as fragile X syndrome, Bannayan-Zonana syndrome, PTEN hamartoma tumor syndrome, Marshall syndrome, Nevo syndrome, mosaic trisomy 8 and Pallister-Killian syndrome.
Antenatal diagnosis
Prenatal diagnosis and/or pre-implantation genetic testing are possible for at-risk pregnancies when a mutation has previously been identified in the family. Prenatal ultrasound examination can detect disproportionate fetal overgrowth, while elevated maternal serum alpha-fetoprotein (AFP) levels may also be useful to suspect SGBS.
Genetic counseling
SGBS follows an X-linked recessive pattern of transmission. In the offspring of an affected male, daughters are heterozygous and sons are unaffected. For each pregnancy, a heterozygous female has a 25% risk of having an affected son and a 25% risk of having a carrier daughter (usually not affected or showing minimal clinical findings due to lyonization). SGBS may also result from de novo mutations (20-30% of cases).
Management and treatment
Management requires a multidisciplinary approach with pediatric cardiologists, neurologists, orthopedics, and speech therapists. Congenital malformations may require surgery. Special attention should be paid to cardiac abnormalities that are responsible for the increased perinatal and infant mortality. Tumor management and follow-up should be performed.
Prognosis
Prognosis depends on the severity of the disease; in the most severe cases, SGBS is life-threatening before birth or in infancy, whereas in milder cases patients often live into adulthood.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Pablo LAPUNZINA | ITHACA* - Dr Jair Antonio TENORIO CASTAÑO

                                * European Reference Network


A rare osteochrondrosis characterized by chronic traction injury of the immature osteotendinous junction where the patellar tendon inserts into the inferior pole of the patella. It is typically seen in active adolescents. Patients present with point tenderness at the inferior pole of the patella associated with focal swelling and restriction of knee joint range of movement. Radiographic features include thickening of the proximal patellar tendon (potentially followed by dystrophic calcification and/or ossification) and fragmentation of the inferior pole of the patella.


Single-organ polyarteritis nodosa (PAN) is a rare, often mild form of PAN characterized by limited disease without generalized manifestations, most often affecting the skin (cutaneous PAN; see this term), the brain, eyes, pancreas, testicles, ureter, breasts, or ovaries. Affected patients are often younger than those with systemic PAN (see this term) and relapses appear to be more common.


Singleton-Merten dysplasia is characterized by dental dysplasia, progressive calcification of the thoracic aorta with stenosis, osteoporosis and expansion of the marrow cavities in hand bones. Additional features included generalized muscle weakness and atrophy, and chronic psoriasiform skin eruptions. It has been reported in four unrelated patients (male and female) and in a family with multiple affected members (male).


Sinoatrial node dysfunction and deafness is a rare genetic disease characterized by congenital severe to profound deafness with no evidence of vestibular dysfunction, associated with sinoatrial node dysfunction with pronounced bradycardia and increased variability of heart rate at rest and episodic syncopes that may be triggered by enhanced physical activity and stress.


A rare, lethal, congenital anomaly that may represent the most severe form of caudal dysgenesia and characterized by fusion of the lower limbs (mermaid-like) always associated with severe genitourinary and gastrointestinal anomalies. Furthermore, there is wide phenotipical variability in the musculoskeletal, central nervous system, cardiopulmonary, anomalies present. Pelvic, sacral and spinal defects , internal and external genitalia defects, renal agenesis, absent bladder, rectal/anal atresia are commonly described. Most cases are stillborn or die during, or shortly after, birth. Sirenomelia can be classified on the basis of limb malformations phenotypes. Due to the similarity, the distinction between sirenomelia and caudal regression syndrome, familial caudal dysgenesis and VACTERL is debated.


Sitosterolemia is a rare autosomal recessive sterol storage disease characterized by the accumulation of phytosterols in the blood and tissues. Clinical manifestations include xanthomas, arthralgia and premature atherosclerosis. Hematological manifestations include hemolytic anemia with stomatocytosis and macrothrombocytopenia. The disease is caused by homozygous or compound heterozygous mutations in ABCG5 (2p21) and ABCG8 (2p21) genes.


A rare, genetic, developmental defect during embryogenesis characterized by a partial mirror-image transposition of intra-thoracic and/or intra-abdominal organs across the left-right axis of the body. Intra-organ variations and other malformations, such as ciliary motricity anomalies (e.g. Kartagener syndrome), biliary atresia and cardiac defects, are frequently associated. Left (polysplenia syndrome) or right (asplenia syndrome) isomerism are usually observed.


A rare, genetic, developmental defect during embryogenesis characterized by total mirror-image transposition of both thoracic and abdominal viscera across the left-right axis of the body. Congenital abnormalities, such as primary ciliary dyskinesia, Kartagener type, polysplenia syndrome, biliary atresia, congenital heart disease, and midgut malrotation, as well as vascular anomalies (e.g. absence of retrohepatic inferior vena cava, preduodenal portal vein, aberrant hepatic arterial anatomy) and malignancy, are frequently associated.


A rare frontonasal dysplasia characterized by a craniofacial phenotype comprising frontal bossing with high anterior hairline, ptosis, hypertelorism, epicanthus inversus, flat nasal bridge, and broad nasal tip. Large anterior fontanelle, sagittal synostosis, and cranial base anomalies have also been described.


A rare neurocutaneous disorder caused by an inborn error of lipid metabolism and characterized by congenital ichthyosis, intellectual deficit, and spasticity.

Summary:
Epidemiology
Prevalence is estimated at 1/250,000 worldwide, but the syndrome is more common in Sweden due to a founder effect.
Clinical description
Clinical features develop perinatally and during infancy. Patients tend to be born preterm. Hyperkeratosis is usually present at birth and progresses to a generalized ichthyosis, particularly prominent on flexural areas, the nape of the neck, the trunk and the extremities. Pruritus is a prominent feature. Erythematous dermatitis is often present at birth, and then tends to fade with increasing age. Neurological signs appear during the first two years of life and consist of delay in reaching motor milestones due to spastic diplegia or, much less commonly, spastic tetraplegia. Approximately one-half of patients are non-ambulatory. Seizures occur in about 40% of cases. Intellectual deficit varies from mild to severe, although rare patients with normal intellect have been reported. Delayed speech and dysarthria are common. Ophthalmologic involvement is often present and is characterized by retinal crystalline inclusions (so-called glistening white dots) surrounding the fovea. Photophobia and myopia are common.
Etiology
SLS is caused by mutations in the ALDH3A2 gene (17p11.2) encoding fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of fatty aldehydes to fatty acids. More than 90 mutations in ALDH3A2 have been identified, including amino acid substitutions, deletions, insertions, splicing errors and contiguous gene deletions.
Diagnostic methods
SLS is diagnosed based on the clinical features, and by measuring FALDH or fatty alcohol oxidoreductase (FAO) activity in cultured fibroblasts from skin biopsies. DNA-based diagnosis is possible by directly sequencing the ALDH3A2 gene and identifying pathogenic mutations.
Differential diagnosis
In early infancy, before the onset of spasticity, the differential diagnosis includes other forms of congenital ichthyosis including lamellar ichthyosis and congenital ichthyosiform erythroderma. Once neurologic symptoms appear, the differential diagnosis includes other neuro-ichthyotic syndromes such as neutral lipid storage disease (Chanarin-Dorfman syndrome), ELOVL4 deficiency, multiple sulfatase deficiency and Refsum disease.
Antenatal diagnosis
Antenatal diagnosis is possible through biochemical or molecular analysis of amniocytes or chorionic villus cells.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management should be multidisciplinary including neurologists, dermatologists, ophthalmologists, orthopedic surgeons, and physiotherapists. The treatment of ichthyosis consists of topical application of moisturizing creams and keratolytic agents, or use of systemic retinoids. Seizures usually respond to anti-convulsant medications and spasticity is alleviated by botulinum toxin injections or surgical procedures. Special diets with medium-chain fatty acid supplements may help the ichthyosis, but effects are limited.
Prognosis
Patients usually survive until adulthood but require life-long care. Minimal progression of the neurologic findings or intellectual deficit occurs after puberty. Patients with early symptoms tend to be more severely affected.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Dr William RIZZO


Skeletal dysplasia-epilepsy-short stature syndrome

A rare, genetic dysostosis malformation syndrome characterized by skeletal dysplasia (rabbit ear-shaped iliac alae, delayed bone age, abnormalities of the vertebral bodies and schisis of the vertebral arches), seizures, short stature, cerebral atrophy and moderate to severe intellectual disability. Additional variable manifestations include corneal and retinal abnormalities, cataract, prognathism, dental malocclusion, brachydactyly, clinodactily, slight generalized hypotonia and hyper extensible joints.


Skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of developmental delay, variable intellectual disability, skeletal dysplasia, and in many cases T-cell immunodeficiency and other immunologic abnormalities. Skeletal findings include short stature, anomalies of the long bones, hands and feet, and pelvis, platyspondyly, cervical malformation, and pectus excavatum. Dysmorphic facial features, such as coarse face, hypertelorism, and broad nasal tip, may be present. Additional reported manifestations are seizures, hyperreflexia, nystagmus, and muscular hypotonia, as well as multiple liver cysts.


Ewing's sarcoma is a malignant small round cell bone tumor with strong metastatic potential.

Summary:
Epidemiology
Annual incidence is estimated at 1/312,500 in children under the age of 15.
Clinical description
It occurs between the ages of 5 and 30 with a peak of incidence between ages 12 and 18. The most frequent symptom is pain. Other symptoms depend on the organs closest to the tumor: motor, sphincteric disorders caused by nervous compression or mechanical disorders are associated with pelvic tumors; respiratory disorders or pleural effusion are associated with costal tumors; medullar or radicular compression are associated with vertebral tumors. The tumor initially develops most frequently in bone, particularly in the pelvis (30%), thorax (rib, clavicle, scapula) (20%), femur (16%), tibia (9%), vertebrae (8%) and humerus (5%). The disease has a high potential for metastases (lung, bone, bone marrow). Neuroepithelioma is a highly differentiated neural variant (see this term). Askin's tumor is a thoracic variant which can be slightly or well differentiated.
Etiology
Although no specific cause has been identified, a specific translocation involving the EWSR1 gene (22q12.2) is present in 90% of tumors of this type, most often a translocation t(11;22)(q24;q29). Many variants of this translocation have been described (involving the ERG, ETV1, FLI1 and NR4A3 genes).
Diagnostic methods
The diagnosis is suggested after the identification, by PCR (polymerase chain reaction), of these translocations.
Differential diagnosis
Differential diagnoses include other small round cell tumors: neuroblastoma, embryonal or alveolar rhabdomyosarcoma, non-Hodgkin's lymphoma and mesenchymatous chondrosarcomas (see these terms). The existence of a translocation involving the EWSR1 gene allows these diseases to be ruled out.
Management and treatment
Treatment should be managed by a multidisciplinary team with expertise in treating childhood cancers. Treatment starts systematically with chemotherapy to reduce the size of the primary tumor and to eradicate or prevent metastases. Surgery is recommended whenever the location of the tumor allows. Local radiotherapy is sometimes necessary, either in addition to surgery or alone for inoperable tumors. For more severe forms of the disease (limited response to initial chemotherapy or metastases already present at diagnosis), high dose chemotherapy with stem cell transplantation can be suggested as a last resort treatment. Targeted therapies, for example with anti-IGF-R (insulin-like growth factor receptor), are currently being studied.
Prognosis
Survival without recurrence of localized forms is around 70%. For forms with lung metastases the survival rate is around 50%. Forms with metastases of the bones or bone marrow have a more severe prognosis.

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Dr Odile OBERLIN


Skin fragility-woolly hair-palmoplantar keratoderma syndrome

A rare, genetic, ectodermal dysplasia syndrome characterized by persistent skin fragility which manifests with blistering and erosions due to minimal trauma, woolly hair with variable alopecia, hyperkeratotic nail dysplasia, diffuse or focal palmoplantar keratoderma with painful fissuring, and no cardiac abnormalities. Perioral hyperkeratosis may also be associated.


SLC35A1-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case by repeated hemorrhagic incidents, including severe pulmonary hemorrhage.


A rare, congenital disorder of glycosylation characterized by severe or profound global developmental delay, early epileptic encephalopathy, muscular hypotonia, dysmorphic features (coarse facies, thick eyebrows, broad nasal bridge, thick lips, inverted nipples), variable ocular defects and brain morphological abnormalities on brain MRI (cerebral atrophy, thin corpus callosum).


A form of spondylodysplastic Ehlers-Danlos syndrome (EDS) due to variants in the SLC39A13 gene and characterized by the presence of thin and finely wrinkled skin of the hands and feet, hypermobile distal joints, characteristic facial features (downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae, microdontia or oligodontia), muscular hypotonia, associated with significant short stature of childhood-onset, ocular findings (myopia and keratoconus) and, more rarely, vascular complications. Mild radiographic changes were observed, among which platyspondyly is a useful diagnostic feature.

Summary:
Epidemiology
To date, 13 individuals with molecularly diagnosed SLC39A13-related spondylodysplastic Ehlers-Danlos syndrome, have been reported.
Clinical description
The main features in affected individuals are significant short stature of childhood-onset, characteristic facial features which may be sufficient to suggest the diagnosis (downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish/greyish sclerae, small mouth, and microdontia or oligodontia), connective tissue weakness affecting mainly the skin and peripheral joints, muscular hypotonia and a moderate skeletal dysplasia. The skin is soft, thin and finely wrinkled, especially on the hands and feet, moderately hyperelastic with bruisability and atrophic scars. Affected patients present moderate hypermobility (especially of the small joints) hands with finely wrinkled palms, thenar and hypothenar atrophy, and tapering fingers. Due to muscular hypotonia, motor development may be slightly delayed, but intelligence in reported cases is normal. Body proportions are normal and post-natal short stature seems to be more intrinsic and represents a true growth failure and not a consequence of bone dysplasia. Skeletal radiographs show mild changes, among which platyspondyly of the thoracic and lumbar spine is a useful diagnostic pointer. Other signs are the following: irregular vertebral end plates, with concave conformation, minor epimetaphyseal alterations in appendicular bones, especially of the distal ulna, diaphyseal overconstriction of radius and ulna. Bowing of limbs, pes planus and osteopenia have been described. Hypodontia and oligodontia are particular features of the disorder. Among the eye findings, myopia has been described in various patients, in addition to keratoconus, particularly dangerous due to the possibility of perforation or rupture. Vascular complications, such as varicose veins of the lower legs and cerebral hemorrhage have been described in the 2 elderly patients.
Etiology
The disorder is due to variants of the SLC39A13 gene (11p11.2), encoding for the zinc transporter protein Zrt- and Irt-like protein 13 (ZIP13) which forms a homo-dimer consisting of 8 transmembrane domains and 4 intracellular loops.
Diagnostic methods
Diagnosis is based on clinical examination, radiological studies and molecular findings.
Differential diagnosis
Differential diagnosis includes other spondylodysplastic Ehlers-Danlos syndromes and genetic conditions with significant short stature of childhood-onset, joint hypermobility, and thin and finely wrinkled skin.
Antenatal diagnosis
Prenatal diagnosis is possible where a known pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management requires a multi-disciplinary approach. Specific regular follow-up is recommended based on the patient's clinical manifestations. Ophthalmologic investigation should be required in all confirmed cases.
Prognosis
Whilst only 3 adult patients have been reported in the literature, data is currently limited with respect to life expectancy. Cerebral hemorrhage has been described in 2 elderly patients; however, it unclear whether this complication is related to the disease and, to date, there are no known reasons to suspect a reduced life expectancy. The functional consequences and quality of life depend on disease severity. The pathology is not progressive.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Livia GARAVELLI | ITHACA* - Dr Gabriele TRIMARCHI | ITHACA*

                                * European Reference Network


A rare congenital disorder of glycosylation characterized by infantile onset of global developmental delay, severe intellectual disability, hypotonia, and variable additional features including short stature, cranial asymmetry, seizures, strabismus, recurrent infections, and osteopenia, among others. Laboratory analysis reveals decreased blood levels of zinc and manganese, as well as an abnormal serum transferrin glycosylation pattern with decreased tetrasialo- and increased asialo-, monosialo-, disialo, and trisialo-transferrin, consistent with a type II congenital disorder of glycosylation. Brain imaging shows cerebellar and/or cerebral atrophy.