MedGen

Shwachman-Diamond syndrome (SDS) is characterized by: exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common. [from GeneReviews]

The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family. [from GeneReviews]

Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, a life-threatening, hyperinflammatory condition. All affected individuals including adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation (HSCT) develop neurologic findings during early adulthood. [from GeneReviews]

X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifest as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum IgG to be achieved, and more liberal use of antibiotics. [from GeneReviews]

Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS. [from GeneReviews]

Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS. [from GeneReviews]

The nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by Fuchshuber et al., 1996). Nephrotic syndrome type 1 (NPHS1) is characterized by prenatal onset of massive proteinuria followed by severe steroid-resistant nephrotic syndrome apparent at birth with rapid progression to end-stage renal failure (Kestila et al., 1998). Because of confusion in the literature regarding use of the terms 'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see NOMENCLATURE section), these disorders in OMIM are classified as NPHS or FSGS according to how they were first designated in the literature. Genetic Heterogeneity of Nephrotic Syndrome and Focal Segmental Glomerulosclerosis Nephrotic syndrome and FSGS are genetically heterogeneous disorders representing a spectrum of hereditary renal diseases. See also NPHS2 (600995), caused by mutation in the podocin gene (604766); NPHS3 (610725), caused by mutation in the PLCE1 gene (608414); NPHS4 (256370), caused by mutation in the WT1 gene (607102); NPHS5 (614199), caused by mutation in the LAMB2 gene (150325); NPHS6 (614196), caused by mutation in the PTPRO gene (600579); NPHS7 (615008), caused by mutation in the DGKE gene (601440); NPHS8 (615244), caused by mutation in the ARHGDIA gene (601925); NPHS9 (615573), caused by mutation in the COQ8B gene (615567); NPHS10 (615861), caused by mutation in the EMP2 gene (602334); NPHS11 (616730), caused by mutation in the NUP107 gene (607617); NPHS12 (616892), caused by mutation in the NUP93 gene (614351); NPHS13 (616893), caused by mutation in the NUP205 gene (614352); NPHS14 (617575), caused by mutation in the SGPL1 gene (603729); NPHS15 (617609), caused by mutation in the MAGI2 gene (606382); NPHS16 (617783), caused by mutation in the KANK2 gene (614610), NPHS17 (618176), caused by mutation in the NUP85 gene (170285); NPHS18 (618177), caused by mutation in the NUP133 gene (607613); NPHS19 (618178), caused by mutation in the NUP160 gene (607614); NPHS20 (301028), caused by mutation in the TBC1D8B gene (301027); NPHS21 (618594) caused by mutation in the AVIL gene (613397); NPHS22 (619155), caused by mutation in the NOS1AP gene (605551); NPHS23 (619201), caused by mutation in the KIRREL1 gene (607428); NPHS24 (619263), caused by mutation in the DAAM2 gene (606627); and NPHS26 (620049), caused by mutation in the LAMA5 gene (601033). The symbol NPHS25 has been used as an alternative designation for NPHS21. See also FSGS1 (603278), caused by mutation in the ACTN4 gene (604638); FSGS2 (603965), caused by mutation in the TRPC6 gene (603652); FSGS3 (607832), associated with variation in the CD2AP gene (604241); FSGS4 (612551), mapped to chromosome 22q12; FSGS5 (613237), caused by mutation in the INF2 gene (610982); FSGS6 (614131), caused by mutation in the MYO1E gene (601479); FSGS7 (616002), caused by mutation in the PAX2 gene (167409); FSGS8 (616032), caused by mutation in the ANLN gene (616027); and FSGS9 (616220), caused by mutation in the CRB2 gene (609720). [from OMIM]

An inherited susceptibility or predisposition to developing aquired partial lipodystrophy. [from MONDO]

FLNA deficiency is associated with a phenotypic spectrum that includes FLNA-related periventricular nodular heterotopia (Huttenlocher syndrome), congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy, dilation and rupture of the thoracic aortic, pulmonary disease (pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis), gastrointestinal dysmotility and obstruction, joint hypermobility, and macrothrombocytopenia. [from GeneReviews]

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord. [from GeneReviews]

Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease. The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated. [from GeneReviews]

The first identified CACNA1C-related disorder, referred to as Timothy syndrome, consists of the combination of prolonged QT interval, autism, and cardiovascular malformation with syndactyly of the fingers and toes. Infrequent findings also include developmental and speech delay, seizures, and recurrent infections. With increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders has been recognized. Because CACNA1C is associated with calcium channel function, all individuals with a pathogenic variant in this gene are at risk for cardiac arrhythmia of a specific type. The clinical manifestations of a CACNA1C-related disorder include three phenotypes: Timothy syndrome with or without syndactyly. QT prolongation (QTc >480 ms) and arrhythmias in the absence of other syndromic features. Short QT syndrome (QTc <350 ms) or Brugada syndrome with short QT interval. These three phenotypes can be separated into two broad categories on the basis of the functional consequences of the pathogenic variants in CACNA1C: QT prolongation with or without a Timothy syndrome-associated phenotype associated with pathogenic variants inducing a gain of function at the cellular level (i.e., increased calcium current). Short QT interval with or without Brugada syndrome EKG pattern associated with pathogenic variants causing loss of function (i.e., reduced calcium current). [from GeneReviews]

Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria. The mild phenotype (~75% of affected males) with onset in the second or third decade of life is typically limited to these biochemical findings, whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia. In the mild phenotype, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled. [from GeneReviews]

Beta-mannosidosis is an autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of lysosomal beta-mannosidase activity. The most severely affected patients show developmental delay and mental retardation, but there are differing levels of severity and some patients may have comparatively mild disease (Bedilu et al., 2002) The disorder was first described in goats (Jones and Dawson, 1981), who have a more severe neurodegenerative disorder than that seen in humans. [from OMIM]

Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder of neutrophil function resulting from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule. The leukocyte cell adhesion molecule is present on the surface of peripheral blood mononuclear leukocytes and granulocytes and mediates cell-cell and cell-extracellular matrix adhesion. LAD is characterized by recurrent bacterial infections; impaired pus formation and wound healing; abnormalities of a wide variety of adhesion-dependent functions of granulocytes, monocytes, and lymphocytes; and a lack of beta-2/alpha-L, beta-2/alpha-M, and beta-2/alpha-X expression. Genetic Heterogeneity of Leukocyte Adhesion Deficiency Also see LAD2 (266265), caused by mutation in the SLC35C1 gene (605881), and LAD3 (612840), caused by mutation in the FERMT3 gene (607901). [from OMIM]

About half of all people with trichothiodystrophy have a photosensitive form of the disorder, which causes them to be extremely sensitive to ultraviolet (UV) rays from sunlight. They develop a severe sunburn after spending just a few minutes in the sun. However, for reasons that are unclear, they do not develop other sun-related problems such as excessive freckling of the skin or an increased risk of skin cancer. Many people with trichothiodystrophy report that they do not sweat.

Trichothiodystrophy is also associated with recurrent infections, particularly respiratory infections, which can be life-threatening. People with trichothiodystrophy may have abnormal red blood cells, including red blood cells that are smaller than normal. They may also have elevated levels of a type of hemoglobin called A2, which is a protein found in red blood cells. Other features of trichothiodystrophy can include dry, scaly skin (ichthyosis); abnormalities of the fingernails and toenails; clouding of the lens in both eyes from birth (congenital cataracts); poor coordination; and skeletal abnormalities including degeneration of both hips at an early age.

Intellectual disability and delayed development are common in people with trichothiodystrophy, although most affected individuals are highly social with an outgoing and engaging personality. Some people with trichothiodystrophy have brain abnormalities that can be seen with imaging tests. A common neurological feature of this disorder is impaired myelin production (dysmyelination). Myelin is a fatty substance that insulates nerve cells and promotes the rapid transmission of nerve impulses.

Mothers of children with trichothiodystrophy may experience problems during pregnancy including pregnancy-induced high blood pressure (preeclampsia) and a related condition called HELLP syndrome that can damage the liver. Babies with trichothiodystrophy are at increased risk of premature birth, low birth weight, and slow growth. Most children with trichothiodystrophy have short stature compared to others their age. 

The signs and symptoms of trichothiodystrophy vary widely. Mild cases may involve only the hair. More severe cases also cause delayed development, significant intellectual disability, and recurrent infections; severely affected individuals may survive only into infancy or early childhood.

In people with trichothiodystrophy, tests show that the hair is lacking sulfur-containing proteins that normally gives hair its strength. A cross section of a cut hair shows alternating light and dark banding that has been described as a "tiger tail."

Trichothiodystrophy, commonly called TTD, is a rare inherited condition that affects many parts of the body. The hallmark of this condition is hair that is sparse and easily broken.  [from MedlinePlus Genetics]

Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguishes Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior. [from GeneReviews]

X-linked lymphoproliferative disease (XLP) has two recognizable subtypes, XLP1 and XLP2. XLP1 is characterized predominantly by one of three commonly recognized phenotypes: Inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis. Dysgammaglobulinemia. Lymphoproliferative disease (malignant lymphoma). XLP2 is most often characterized by HLH (often associated with EBV), dysgammaglobulinemia, and inflammatory bowel disease. HLH resulting from EBV infection is associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Dysgammaglobulinemia is typically hypogammaglobulinemia of one or more immunoglobulin subclasses. The malignant lymphomas are typically B-cell lymphomas, non-Hodgkin type, often extranodal, and in particular involving the intestine. [from GeneReviews]

Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.

Mevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).

During episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy.

People with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy. [from MedlinePlus Genetics]

FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals. [from GeneReviews]