A rare genetic skin disease characterized by infantile onset of diffuse alopecia, abnormal skin pigmentation (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), palmoplantar keratoderma, and nail dystrophy. Patients develop recurrent spinocellular carcinomas later in life. Brittle teeth resulting in early loss of dentition have also been described.
Heterozygous mutation in the SASH1 gene results in dyschromatosis universalis hereditaria-1 (DUH1; 127500). Description CAPOK syndrome is characterized by onset of symptoms in the first year of life, with the development of progressive alopecia, hypo- and hyperpigmented macular skin lesions, palmoplantar keratoderma, and nail dystrophy. ... Molecular Genetics By genomewide homozygosity mapping and exome sequencing in a Moroccan brother and sister with CAPOK syndrome, Courcet et al. (2015) identified homozygosity for a missense mutation in the SASH1 gene (E617K; 607955.0004) that segregated with disease in the family and was not found in local exomes or public variant databases.
A rare genetic neurological disorder characterized by the association of hypomyelinating leukodystrophy with spondylometaphyseal dysplasia. Patients present in infancy with absent or delayed ability to walk independently, slowly progressive motor deterioration, spasticity, ataxia, proximal weakness, and joint contractures. Additional manifestations include mild cognitive impairment, short stature, scoliosis, enlarged and deformed joints, dysarthria, nystagmus, visual defects, and mildly dysmorphic features, among others. Mode of inheritance is X-linked recessive.
Clinical Features Neubauer et al. (2006) reported a 3-generation family from northern Germany in which 4 males had a disorder characterized by early-onset leukoencephalopathy associated with metaphyseal chondrodysplasia. Inheritance was consistent with an X-linked recessive pattern. The proband developed normally until age 2 to 3 years, when he developed slow gait and toe-walking. Broad knees and wrists were noted. In the following years, he developed a fine tremor and deteriorating vision. Examination at age 11 years showed spastic paraplegia, hyperreflexia with extensor plantar responses, action tremor, and an IQ of 65 to 70. He had a low nasal bridge, mild midface hypoplasia, and anteverted nares.
Clinical Features Bieganski et al. (1999) described a distinct form of spondyloepimetaphyseal dysplasia in 3 boys related through their mothers, in a pattern clearly consistent with X-linked recessive inheritance. The main clinical features were short stature, abnormal face, skeletal deformities, and progressive mental retardation. Radiologically, there were epimetaphyseal changes and spine involvement. Brachydactyly was present in the hands and feet. The children were normal at birth. One of the affected males was bedridden at the age of 16 years; he had dysarthric speech, uncoordinated eye movements, sporadically occurring partial left-sided seizures, and joint contractures.
Patients typically present with nonspecific symptoms, such as chest pain, cough, shortness of breath, or in some cases, superior vena cava syndrome, although patients could be asymptomatic during the early stages or present with multiple endocrine neoplasia type I. Ectopic production of ACTH and serotonin can lead to Cushing syndrome and carcinoid syndrome, respectively.
A rare systemic disease characterized by characterized by acute or subacute onset of thrombocytopenia, anasarca (edema, pleural effusion, ascites), and systemic inflammation (fever and/or elevated C-reactive protein). Minor diagnostic categories are Castleman's disease-like features on lymph node biopsy, reticulin myelofibrosis and/or increased number of megakaryocytes in bone marrow, progressive renal insufficiency, and mild organomegaly including hepatosplenomegaly and lymphadenopathy. Most patients show elevated levels of serum alkaline phosphatase, while marked polyclonal hypergammopathy is rare.
A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by either late-onset myopathy with progressive external ophthalmoplegia and muscular weakness (predominantly limb-girdle) or early-onset myopathy presenting with decreased fetal movements, congenital ptosis, progressive external ophthalmoplegia, hypotonia and, variably, joint contractures. Reduced content and multiple deletions of mitochondrial DNA is observed in muscle biopsy.
A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) is caused by heterozygous mutation in the DNA2 gene (601810) on chromosome 10q. Description PEOA6 is characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA (mtDNA) deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression (summary by Ronchi et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). Clinical Features Ronchi et al. (2013) reported 2 sibs and 2 unrelated patients with PEOA6.
A subgroup of therapy-related myeloid neoplasms (t-MN), associated with treatment of an unrelated neoplastic disease with radiation. The neoplastic cells typically harbor unbalanced aberrations of chromosomes 5 and 7 (monosomy 5/del(5q) and monosomy 7/del(7q)) or a complex karyotype. Patients frequently present with multilineage dysplasia and cytopenias 5-10 years after exposure.
A rare genetic immune disease characterized by infantile or childhood onset of combined immunodeficiency with recurrent viral, bacterial, and fungal infections, severe autoimmunity mainly manifesting as antibody-mediated destruction of red blood cells, platelets, and neutrophils, and mild to moderate developmental delay. Laboratory findings include decreased circulating T-, B-, and natural killer cells, and hypergammaglobulinemia.
A rare, genetic, neurodegenerative disease characterized by normal early development followed by childhood onset optic atrophy with progressive vision loss and eventually blindness, followed by progressive neurological decline that typically includes cerebellar ataxia, nystagmus, dorsal column dysfunction (decreased vibration and position sense), spastic paraplegia and finally tetraparesis.
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-79 (SPG79) is caused by by homozygous or compound heterozygous mutation in the UCHL1 gene (191342) on chromosome 4p13. Description SPG79 is an autosomal recessive progressive neurologic disorder characterized by onset of spastic paraplegia and optic atrophy in the first decade of life. Additional features are variable, but may include peripheral neuropathy, cerebellar ataxia, and cognitive impairment (summary by Rydning et al., 2017). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800). Clinical Features Nyberg-Hansen and Refsum (1972) reported 2 brothers, born of unrelated Norwegian parents, with onset of progressive lower and upper limb spasticity in early childhood, followed by onset of progressive visual failure, myopia, and optic atrophy at age 10 years.
A rare, severe, circulatory system disease characterized by premature, diffuse, severe atherosclerosis (including the aorta and renal, coronary, and cerebral arteries), sensorineural deafness, diabetes mellitus, progressive neurological deterioration with cerebellar symptoms and photomyoclonic seizures, and progressive nephropathy. Partial deficiency of mitochondrial complexes III and IV in the kidney and fibroblasts (but not in muscle) may be associated. There have been no further descriptions in the literature since 1994.
Many of the features were similar to those in Herrmann syndrome (172500), but that condition appeared to be autosomal dominant and there were different pathologic findings, namely, PAS-positive deposits in the dentate and olivary nuclei as well as the renal collecting tubules.
49,XYYYY is a rare Y chromosome number anomaly with a variable phenotype mainly characterized by moderate to severe intellectual disability, speech delay, hypotonia, and mild dysmorphic features, including facial asymmetry, hypertelorism, bilateral low set 'lop' ears, and micrognatia. Skeletal abnormalities (such as skull deformities, radioulnar synostosis, elbow flexion, clinodactyly, brachydactyly) and behavourial problems have also been associated with this condition. Genitalia are normal at birth, although hypogonadism and azoospermia has been reported in adults.
A rare genetic disease characterized by childhood onset of multiple endocrine manifestations in combination with central and peripheral nervous system abnormalities. Reported signs and symptoms include postnatal growth retardation, moderate intellectual disability, hypogonadotropic hypogonadism, insulin-dependent diabetes mellitus, central hypothyroidism, demyelinating sensorimotor polyneuropathy, and cerebellar and pyramidal signs. Progressive hearing loss and a hypoplastic pituitary gland have also been described. Brain imaging shows moderate white matter abnormalities.
A number sign (#) is used with this entry because of evidence that the polyendocrine-polyneuropathy syndrome (PEPNS) is caused by homozygous mutation in the DMXL2 gene (612186) on chromosome 15q21.2. ... Tata et al. (2014) noted overlap between the features exhibited by affected individuals in the Senegalese family and the phenotypes of the Warburg Micro (see 600118) and Martsolf (212720) syndromes, which are caused by mutations in genes (RAB3GAP1, 602536 and RAB3GAP2, 609275, respectively) encoding components of the protein complex containing DMXL2. ... INHERITANCE - Autosomal recessive GROWTH Height - Short stature Other - Postnatal growth retardation HEAD & NECK Head - Partial frontal alopecia Ears - Progressive hearing loss Nose - Normal sense of smell GENITOURINARY External Genitalia (Male) - Small testicular volume SKIN, NAILS, & HAIR Hair - Partial frontal alopecia NEUROLOGIC Central Nervous System - Mental retardation, moderate - Dysarthria - Dystonia - Ataxia - Pyramidal syndrome - Subcortical temporal white matter disease, moderate - Cerebellar hypoplasia, mild (in some patients) - Hypoplastic pituitary gland (in some patients) Peripheral Nervous System - Peripheral demyelinating polyneuropathy - Motor delay ENDOCRINE FEATURES - Hypogonadotropic hypogonadism - Low testosterone levels - Low luteinizing hormone levels - Low follicle-stimulating hormone levels - Central hypothyroidism - Low free-T4 levels - Normal thyroid-stimulating hormone level - Episodic asymptomatic severe hypoglycemia in childhood - Nonautoimmune insulin-dependent diabetes in second decade of life MISCELLANEOUS - One consanguineous Senegalese family has been reported (last curated December 2014) MOLECULAR BASIS - Caused by mutation in the DMX-like 2 gene (DMXL2, 612186.0001 ) ▲ Close
A rare genetic systemic or rheumatologic disease characterized by interstitial lung disease (often with pulmonary hemorrhage) and inflammatory arthritis, associated with high-titer autoantibodies (including anti-nuclear and anti-neutrophil cytoplasmic antibodies, and rheumatoid factor). Patients present from infancy to adolescence with tachypnea, cough, hemoptysis, and/or joint pain. Some patients may also develop glomerular disease.
Pulmonary atresia with intact ventricular septum (PA-IVS) is a rare form of cyanotic congenital heart malformation characterized by severe cyanosis and tachypnea. PA-IVS presents significant morphologic diversity: at the end of the spectrum are patients with a mildly hypoplastic and tripartite right ventricle (RV) and mild tricuspid valve (TV) hypoplasia, and at the other end are patients with severe RV and TV hypoplasia, often with RV-dependent coronary circulation.
Pulmonary atresia with intact ventricular septum accounts for less than 3% of all congenital heart defects (Grossfeld et al., 1997). Chitayat et al. (1992) reported 2 sisters with hypoplastic right heart and pulmonary atresia. The first sib was found in the newborn period to have this abnormality. An attempt at surgical repair was unsuccessful. In the next pregnancy, fetal echocardiography at 22 weeks of gestation demonstrated the same cardiac abnormalities, which were confirmed at autopsy in the fetus. No other malformations were found in either case and no other relatives were affected.
A rare congenital disorder of glycosylation characterized by early onset of hypotonia, severe global developmental delay, intellectual disability, and seizures. Ataxia, mild facial dysmorphism, and autistic behavior have also been reported. Brain MRI findings are variable and include cerebral atrophy, cerebellar hypoplasia/atrophy, and thin corpus callosum.
A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-53 (MRT53) is caused by homozygous or compound heterozygous mutation in the PIGG gene (616918) on chromosome 4p16. Description Autosomal recessive mental retardation-53 is a neurodevelopmental disorder characterized by severely delayed psychomotor development, hypotonia apparent since infancy, and early-onset seizures in most patients. Some patients may have additional features, such as cerebellar hypoplasia and ataxia. MRT53 is one of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway (summary by Makrythanasis et al., 2016). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
The CDG (Congenital Disorders of Glycosylation) syndromes are a group of autosomal recessive disorders affecting glycoprotein synthesis. CDG syndrome type Ie is characterised by psychomotor delay, seizures, hypotonia, facial dysmorphism and microcephaly. Ocular anomalies are also very common. Epidemiology The syndrome has been described in seven children.
A number sign (#) is used with this entry because congenital disorder of glycosylation type Ie is caused by homozygous or compound heterozygous mutation in the DPM1 gene (603503) on chromosome 20q13. Description Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. For a general discussion of CDGs, see CDG Ia (212065) and CDG Ib (602579). Clinical Features Kim et al. (2000) reported 2 patients with phenotypic and biochemical features consistent with a congenital disorder of glycosylation.
Primary ciliary dyskinesia - retinitis pigmentosa is an X-linked ciliary dysfunction of both respiratory epithelium and photoreceptors of the retina leading to ocular disorders (mild night blindness, constriction of the visual field, and scotopic and photopic ERG responses reduced to 30-60%) associated with primary ciliary dyskinesia (see this term) manifestations (chronic bronchorrhea with bronchoectasis and chronic sinusitis) and sensorineural hearing loss.
Clinical Features In a family with X-linked retinitis pigmentosa with recurrent respiratory infections, van Dorp et al. (1992) identified, by electron microscopy, nasal ciliary abnormalities in some affected males, consisting of deficient inner dynein arms, incomplete microtubules, and disorientation of cilia, associated with recurrent respiratory infections indistinguishable from immotile cilia syndrome (see 244400). Infertility of the affected males was not a feature. ... Abnormalities of cilia have been reported in X-linked and autosomal types of RP, including Usher syndrome (276900, 276901) (Arden and Fox, 1979; Fox et al., 1980; Hunter et al., 1988). ... The phenotype overlapped those described for primary ciliary dyskinesia and Usher syndrome (276900) and provided support for an essential ciliary function for RPGR in the retina and other tissues. ... A deceased great-great maternal uncle had been diagnosed with Usher syndrome, and the maternal grandmother had 'late-onset' retinitis pigmentosa and sensorineural hearing loss.
A rare, primary bone dysplasia characterized by prenatal and postnatal growth retardation, short stature, cortical thickening and medullary stenosis of the long bones, absent diploic space in the skull bones, hypocalcemia due to the hypoparathyroidism, small hands and feet, delayed mental and motor development, intellectual disability, dental anomalies, and dysmorphic features, including prominent forehead, small deep-set eyes, beaked nose, and micrognathia.
An extremely rare, autosomal dominant immunological disorder characterized by variable enteropathy, endocrine disorders (e.g. type 1 diabetes mellitus, hypothyroidism), immune dysregulation with pulmonary and blood-borne bacterial infections, and fungal infections (chronic mucocutaneous candidiasis) developing in infancy. Other manifestations include short stature, eczema, hepatosplenomegaly, delayed puberty, and osteoporosis/osteopenia.
A number sign (#) is used with this entry because immunodeficiency-31C (IMD31C) is caused by heterozygous mutation in the STAT1 gene (600555) on chromosome 2q32. Immunodeficiency-31A (IMD31A; 614892), an autosomal dominant disorder, and immunodeficiency-31B (IMD31B; 613796), an autosomal recessive disorder, are allelic. Description IMD31C is disorder of immunologic dysregulation with highly variable manifestations resulting from autosomal dominant gain-of-function mutations in STAT1 (600555). Most patients present in infancy or early childhood with chronic mucocutaneous candidiasis (CMC). Other highly variable features include recurrent bacterial, viral, fungal, and mycoplasmal infections, disseminated dimorphic fungal infections, enteropathy with villous atrophy, and autoimmune disorders, such as hypothyroidism or diabetes mellitus.
The diagnosis of THOC6 intellectual disability syndrome is established in a proband with biallelic pathogenic variants in THOC6 identified by molecular genetic testing. ... Genetic counseling. THOC6 intellectual disability syndrome is inherited in an autosomal recessive manner. ... Prevalence As of early 2020, seven years after this syndrome was first described and molecularly explained, 19 affected individuals have been reported in the literature. Initially reported in the Hutterite population [Boycott et al 2010], THOC6 intellectual disability syndrome has now been identified in individuals worldwide. ... See OMIM Phenotypic Series: Autosomal dominant ID; Autosomal recessive ID; Nonsyndromic X-linked ID; and Syndromic X-linked ID. Table 3. Genes of Interest in the Differential Diagnosis of THOC6 Intellectual Disability Syndrome View in own window Gene(s) Disorder MOI Clinical Features of Differential Diagnosis Disorder Overlapping w/ THOC6 ID syndrome Distinguishing from THOC6 ID syndrome ATR CENPJ CEP152 CEP63 DNA2 NIN NSMCE2 RBBP8 TRAIP Seckel syndrome (OMIM PS210600) AR ID; microcephaly; dental malocclusion Severe growth restriction; characteristic facies CREBBP EP300 Rubinstein-Taybi syndrome AD 1 ID; microcephaly; genitourinary anomalies; low-hanging columella Broad angulated thumbs & halluces; downslanting palpebral fissures & grimacing smile EMG1 Bowen-Conradi syndrome (OMIM 211180) AR Severe ID, microcephaly, & micrognathia; founder effect in Hutterite population Multiple joint contractures; severe growth restriction; early mortality KIF7 Acrocallosal syndrome (OMIM 200990) AR Severe ID; corpus callosum dysgenesis; genital anomalies Distal anomalies of limbs; macrocephaly w/protruding forehead & occiput ZEB2 Mowat-Wilson syndrome AD 1 Severe ID; microcephaly; corpus callosum dysgenesis; genitourinary anomalies; congenital heart defects Hirschsprung disease or chronic constipation; distinctive facial features (uplifted earlobes, widely spaced eyes, prominent & pointed chin) AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance 1.
A number sign (#) is used with this entry because of evidence that Beaulieu-Boycott-Innes syndrome (BBIS) is caused by homozygous or compound heterozygous mutation in the THOC6 gene (615403) on chromosome 16p13. Description Beaulieu-Boycott-Innes syndrome (BBIS) is an autosomal recessive neurodevelopmental disorder characterized by delayed development, moderate to severe intellectual disability, and dysmorphic facial features. ... Boycott et al. (2010) noted that a specific cognitive profile appeared to be a feature of this syndrome: the 3 adult patients could read at grade level 4 but demonstrated extreme weakness in mathematics and tasks involving spatial reasoning.
A rare, autosomal recessive, syndromic intellectual disability disorder characterized by global development delay, mild microcephaly, mild to severe intellectual disability and non-specific facial dysmorphism in association with variable multiple congenital anomalies including congenital heart defects, dental anomalies, cryptorchidism, renal and cerebral malformations. ... More rarely, affected individuals could have hypergonadotropic hypogonadism (in females), seizures, low birth weight, feeding difficulties, hearing loss and/or eye abnormalities. Etiology The syndrome is caused by homozygous mutations in THOC6 , encoding for a protein of the THO/TREX (transcription/export) complex, which is involved in the transcription of mRNA as well as the export of spliced mRNA from the nucleus; it is supposed to play a crucial role in both embryogenesis and human neurodevelopment. ... Differential diagnosis Due to the non-specific characteristics of the syndrome, all disorders with intellectual disability and without other distinctive features should be investigated.