Delayed speech and language development, and Pheochromocytoma

Medium match RUBINSTEIN-TAYBI SYNDROME 1; RSTS1

Rubinstein-Taybi syndrome is a multiple congenital anomaly syndrome characterized by mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. The facial appearance is striking, with highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, mild micrognathia, and characteristic grimacing or abnormal smile. Affected individuals also have an increased risk of tumor formation (Rubinstein and Taybi, 1963; review by Hennekam, 2006).Floating-Harbor syndrome (OMIM ), which shows phenotypic overlap with Rubinstein-Taybi syndrome, is caused by mutation in the SRCAP gene (OMIM ), a coactivator for CREBBP. Genetic Heterogeneity of Rubinstein-Taybi SyndromeRubinstein-Taybi syndrome-1 (RSTS1) constitutes about 50 to 70% of patients with the disorder. Rubinstein-Taybi syndrome-2 (RSTS2 ) comprises about 3% of patients and is primarily due to de novo heterozygous mutation in the EP300 gene (OMIM ) on chromosome 22q13 (Bartsch et al., 2010).See also chromosome 16p13.3 deletion syndrome (OMIM ), a severe form of Rubinstein-Taybi syndrome resulting from a contiguous gene deletion involving the CREBBP gene as well as other neighboring genes.

RUBINSTEIN-TAYBI SYNDROME 1; RSTS1 Is also known as rubinstein syndrome, broad thumbs and great toes, characteristic facies, and mental retardation, broad thumb-hallux syndrome

• Autosomal dominant inheritance
• Intellectual disability
• Seizures
• Short stature
• Generalized hypotonia

SOURCES: OMIM

Low match MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB; MEN2B

Multiple endocrine neoplasia type IIB (MEN2B) is an autosomal dominant hamartoneoplastic syndrome characterized by aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas, and thickened corneal nerves. Most affected individuals have characteristic physical features, including full lips, thickened eyelids, high-arched palate, and marfanoid habitus. Other more variable features include skeletal anomalies and gastrointestinal problems (review by Morrison and Nevin, 1996).For a discussion of genetic heterogeneity of multiple endocrine neoplasia (MEN), see MEN1 (OMIM ).

MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB; MEN2B Is also known as men iib, neuromata, mucosal, with endocrine tumors, wagenmann-froboese syndrome, multiple endocrine neoplasia, type iii, formerly;men3, formerly;men2b; multiple endocrine neoplasia type 3; wagenmann-froboese syndrome

• Autosomal dominant inheritance
• Seizures
• Global developmental delay
• Generalized hypotonia
• Scoliosis

SOURCES: ORPHANET SCTID OMIM UMLS ICD10

Low match NEUROFIBROMATOSIS, TYPE I; NF1

Neurofibromatosis type I is an autosomal dominant disorder characterized by cafe-au-lait spots, Lisch nodules in the eye, and fibromatous tumors of the skin. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors. NF1 is sometimes referred to as 'peripheral neurofibromatosis.' The worldwide incidence of NF1 is 1 in 2,500 to 1 in 3,000 individuals (reviews by Shen et al., 1996 and Williams et al., 2009).Type II neurofibromatosis (NF2 ) is a genetically distinct disorder caused by mutation in the gene encoding merlin (NF2 ) on chromosome 22q12. NF2, sometimes known as 'central neurofibromatosis,' is characterized by bilateral acoustic neuroma and meningioma, but few skin lesions or neurofibromas (Rouleau et al., 1993).Some patients with homozygous or compound heterozygous mutations in mismatch repair genes (see, e.g., MLH1; {120436} and MSH2; {609309}) have a phenotype characterized by early onset malignancies and mild features of NF1, especially cafe-au-lait spots; this is known as the mismatch repair cancer syndrome (OMIM ), sometimes referred to as brain tumor-polyposis syndrome-1 or Turcot syndrome. These patients typically do not have germline mutations in the NF1 gene, although a study by Wang et al. (2003) suggested that biallelic mutations in mismatch repair genes may cause somatic mutations in the NF1 gene, perhaps resulting in isolated features resembling NF1.See also Legius syndrome (OMIM ), a genetically distinct disorder with a similar phenotype to NF1.

NEUROFIBROMATOSIS, TYPE I; NF1 Is also known as neurofibromatosis, peripheral type, von recklinghausen disease;von recklinghausen disease due to nf1 mutation or intragenic deletion

• Autosomal dominant inheritance
• Intellectual disability
• Seizures
• Short stature
• Pica

SOURCES: ORPHANET ICD10 OMIM

Low match NEUROFIBROMATOSIS-NOONAN SYNDROME; NFNS

NEUROFIBROMATOSIS-NOONAN SYNDROME; NFNS Is also known as noonan-neurofibromatosis syndrome, neurofibromatosis with noonan phenotype

• Autosomal dominant inheritance
• Global developmental delay
• Short stature
• Pica
• Scoliosis

SOURCES: OMIM ORPHANET

Low match COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 15; COXPD15

Combined oxidative phosphorylation defect type 15 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by onset in infancy or early childhood of muscular hypotonia, gait ataxia, mild bilateral pyramidal tract signs, developmental delay (affecting mostly speech and coordination) and subsequent intellectual disability. Short stature, obesity, microcephaly, strabismus, nystagmus, reduced visual acuity, lactic acidosis, and a brain neuropathology consistent with Leigh syndrome are also reported.

COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 15; COXPD15 Is also known as ;coxpd15

• Autosomal recessive inheritance
• Seizures
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: UMLS ORPHANET OMIM MONDO

Low match CHROMOSOME 17q11.2 DELETION SYNDROME, 1.4-MB

Approximately 5 to 20% of all patients with neurofibromatosis type I (OMIM ) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).

CHROMOSOME 17q11.2 DELETION SYNDROME, 1.4-MB Is also known as neurofibromatosis 1 microdeletion syndrome, nf1 microdeletion syndrome, van asperen syndrome;dup(17)(q11.2); grisart-destrée syndrome; trisomy 17q11.2

• Autosomal dominant inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Short stature

SOURCES: GARD ORPHANET DOID OMIM MONDO

Low match HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1; HHF1

Familial hyperinsulinism, also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur (Thornton et al., 1998). Genetic Heterogeneity of Hyperinsulinemic HypoglycemiaHHF2 (OMIM ) is caused by mutation in the KCNJ11 gene (OMIM ), on chromosome 11p15.1. HHF3 (OMIM ) is caused by mutation in the glucokinase gene (GCK ) on chromosome 7p15-p13. HHF4 (OMIM ) is caused by mutation in the HADH gene (OMIM ) on chromosome 4q22-q26. HHF5 (OMIM ) is caused by mutation in the insulin receptor gene (INSR ) on chromosome 19p13.2. HHF6 (OMIM ) is caused by mutation in the GLUD1 gene (OMIM ) on chromosome 10q23.3. HHF7 (OMIM ) is caused by mutation in the SLC16A1 (OMIM ) on chromosome 1p13.2-p12. There is evidence of further genetic heterogeneity of HHF.

HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 1; HHF1 Is also known as persistent hyperinsulinemic hypoglycemia of infancy;phhi, hypoglycemia, hyperinsulinemic, of infancy, hyperinsulinemic hypoglycemia due to focal adenomatous hyperplasia, nesidioblastosis of pancreas, hyperinsulinism, familial, with pancreatic nesidioblastosis, hyperinsulinism, congenital

• Autosomal recessive inheritance
• Autosomal dominant inheritance
• Intellectual disability
• Pica
• Milia

SOURCES: OMIM

Low match CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE B; CMTRIB

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

CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE B; CMTRIB Is also known as charcot-marie-tooth neuropathy, recessive intermediate b;ri-cmtb;ri-cmt type b

• Autosomal recessive inheritance
• Global developmental delay
• Peripheral neuropathy
• Hyporeflexia
• Areflexia

SOURCES: OMIM UMLS GARD ORPHANET MONDO DOID

Low match PARAGANGLIOMAS 5; PGL5

• Autosomal dominant inheritance
• Neoplasm
• Hypertension
• Hyperhidrosis
• Tachycardia

SOURCES: OMIM MONDO UMLS

Low match MACROCEPHALY/MEGALENCEPHALY SYNDROME, AUTOSOMAL RECESSIVE; MGCPH

Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).

• Autosomal recessive inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Cognitive impairment

SOURCES: OMIM UMLS MONDO MESH GARD