| #249420 | |||||||||||||||||||||||||||||||||
| FRANK-TER HAAR SYNDROME; FTHS | |||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||
| TER HAAR SYNDROME MELNICK-NEEDLES SYNDROME, AUTOSOMAL RECESSIVE, FORMERLY | |||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||
| TEXT | |||||||||||||||||||||||||||||||||
| A number sign (#) is used with this entry because Frank-ter Haar syndrome is caused by homozygous mutations in the TKS4 gene (SH3PXD2B; 613293) on chromosome 5q35. | |||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||
| The primary characteristics of the Frank-ter Haar syndrome are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by Maas et al., 2004). | |||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||
| Frank et al. (1973) described an 18-month-old Bedouin girl, born to consanguineous parents, with megalocornea, multiple skeletal anomalies, and developmental delay, and suggested that this combination of anomalies was a hitherto unreported entity. Ter Haar et al. (1982) described 3 cases in which the bone changes and facial features (big eyes, micrognathia) were thought to be consistent with the diagnosis of Melnick-Needles syndrome; see 309350. Associated anomalies (bilateral glaucoma in 1 and congenital heart defect in 2) brought them to medical attention. Delay in closure of the anterior fontanel and sclerosis of the base of the skull and mastoids were described. The 'precocious osteodysplasia' of Danks, Mayne, and Kozlowski (see 259270) is an autosomal recessive disorder that bears some similarities. See also entries for serpentine fibula-polycystic kidney syndrome (600330) and megalocornea-mental retardation syndrome (249310) for descriptions of similar entities. Billette de Villemeur et al. (1992) reported a girl, the child of consanguineous parents, with congenital glaucoma, hypertelorism, short saddle nose, micrognathia, flexion deformity of fingers, unilateral clubfoot, widely open fontanels, ventricular septal defect, and motor retardation. She died at 21 months. A brother, who died at 1 year, had the same condition. Hamel et al. (1995) reported a patient with congenital glaucoma, brachycephaly with flat occiput, large anterior fontanel, hypertelorism, anteverted nostrils, thoracolumbar kyphosis, prominent coccyx with skin fold, short hands and feet, flexion deformity of fingers, and clubfeet. He had a double-outlet right ventricle with ventricular septal defect, and severe tricuspid insufficiency. Mild skeletal changes included short tubular bones, absence of distal phalanges of toes, caliber variation of ribs, and scalloping of the anterior surface of the vertebrae. The patient died at 21 months. He belonged to the same extended family as 3 similarly affected patients described by ter Haar et al. (1982) as representing an autosomal recessive form of Melnick-Needles syndrome. Hamel et al. (1995) believed this diagnosis was no longer tenable. They stated that although the craniofacial and radiologic resemblance of their patient and the 3 of ter Haar et al. (1982) to the Melnick-Needles syndrome was striking, the presence of congenital glaucoma, prominent coccyx with skin fold, and early death due to severe cardiovascular anomalies justified the conclusion that these 4 patients do not have a form of Melnick-Needles syndrome. Hamel et al. (1995) stated that their cases, the 3 reported by ter Haar et al. (1982), and the patient described by Billette de Villemeur et al. (1992) all had the same syndrome, an autosomal recessive syndrome for which they proposed the name ter Haar syndrome. Wallerstein et al. (1997) described a boy with ter Haar syndrome, the offspring of Puerto Rican parents who were first cousins once removed. He was followed through the age of 13 years and at that time was reported to be the oldest patient with the disorder. Among the patients reported by ter Haar et al. (1982), Hamel et al. (1995), and Wallerstein et al. (1997), only the patient of Wallerstein et al. (1997) was reported to have developmental delay. Megarbane et al. (1997) reported a family with first-cousin Syrian parents in which 2 children presented with congenital glaucoma, large anterior fontanel, prominent forehead, hypertelorism, downslanting palpebral fissures, broad and flat nasal bridge, broad nasal tip, anteverted nostrils, high-arched palate, gingival hypertrophy, pectus excavatum, prominent coccyx with skin fold, short fingers and toes, single palmar creases, flexion deformities of fingers, clubfeet, and osseous malformations. The eyes showed bilateral severe buphthalmos. Megarbane et al. (1997) concluded that their 2 patients and the patients described by ter Haar et al. (1982), Billette de Villemeur et al. (1992), and Hamel et al. (1995) all had ter Haar syndrome. Rosser et al. (1996) described 3 patients with features common to serpentine fibula syndrome (SFS; 600330) and Frank-ter Haar syndrome. Maas et al. (2004) suggested that the patients of Rosser et al. (1996) probably had Frank-ter Haar syndrome. AlKaissi et al. (2003) reported brother and sister, whose parents were distantly related, with congenital glaucoma, short stature, and mental retardation. Similarities were noted with ter Haar syndrome, but severe mental retardation was an additional feature. Maas et al. (2004) delineated the entity they referred to as Frank-ter Haar syndrome in a report on 4 additional patients, including 3 sibs of Turkish descent. The authors noted that some manifestations such as progressive 'coarsening' of the face, hirsutism, gallstones, lingual papillomatosis, and cardiac valve abnormalities pointed to a possible metabolic basis for the disorder. | |||||||||||||||||||||||||||||||||
| Inheritance | |||||||||||||||||||||||||||||||||
| Autosomal recessive inheritance of Frank-ter Haar syndrome was confirmed by Iqbal et al. (2010). | |||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||
| Iqbal et al. (2010) performed homozygosity mapping in 16 patients from 12 apparently unrelated families with Frank-ter Haar syndrome, including the Dutch family originally described by ter Haar et al. (1982), and identified a 0.27-Mb region of shared homozygosity on chromosome 5q35.1. | |||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||
| In the Lebanese family of Syrian origin with Frank-ter Haar syndrome originally reported by Megarbane et al. (1997), Iqbal et al. (2010) analyzed SNP array data for copy number variation and identified a homozygous deletion on chromosome 5q in affected individuals. The smallest interval overlapping a region of shared homozygosity identified in other FTHS families contained only 1 gene, SH3PXD2B (613293). Iqbal et al. (2010) screened the SH3PXD2B gene in probands from 12 FTHS families and identified 4 homozygous mutations in 6 families (613293.0001-613293.0004), including the Dutch family originally described by ter Haar et al. (1982) (see 613293.0001) and the Turkish family originally reported by Maas et al. (2004) (see 613293.0002). No mutations were found in the 6 remaining FTHS probands, including the Puerto Rican boy previously described by Wallerstein et al. (1997). Iqbal et al. (2010) noted that mutations in cis-regulatory elements might have been missed in those families, and in keeping with this hypothesis, TKS4 protein was present in fibroblasts from the Puerto Rican patient, but at markedly reduced levels compared to controls. In some of the mutation-negative FTHS families, other regions of homozygosity had also been found, consistent with possible genetic heterogeneity. | |||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||
| Iqbal et al. (2010) used a gene-trap strategy to generate Sh3pxd2b (613293)-null mice and observed pronounced skeletal, eye, and cardiac abnormalities that phenocopied the majority of the defects associated with Frank-ter Haar syndrome. Mao et al. (2011) studied the eyes of the nee strain of mice, which carry a spontaneously arising mutation in Sh3pxd2b, to determine whether the mice developed glaucoma. From an early age, nee mice uniformly exhibited severe, circumferential iridocorneal adhesions, blocking aqueous humor outflow. By 3 to 4 months of age, they exhibited high intraocular pressure (30.8 + 12.5 mm Hg), corneal opacity, and enlarged anterior chambers with progressive retinal ganglion cell loss, optic nerve head excavation, and axon loss. Thus, the eyes of nee mice exhibited anterior segment dysgenesis and early-onset glaucoma. Mao et al. (2011) concluded that because SH3PXD2B was predicted to be a podosome adaptor protein, their findings implicated podosomes in the normal development of the iridocorneal angle and the genes influencing podosomes as candidates in glaucoma. Mao et al. (2011) also postulated that because of the early-onset, high-penetrance glaucoma, nee mice offered many potential advantages as a new mouse model of glaucoma. | |||||||||||||||||||||||||||||||||
| History | |||||||||||||||||||||||||||||||||
| Melnick-Needles syndrome (309350) is a disorder of generalized bone dysplasia characterized by cortical irregularity and shortness and bowing of the long bones with metaphyseal flare, inherited in an X-linked dominant pattern with, usually, lethality in hemizygous males. It is caused by mutation in the filamin A gene (300017). Two of the 3 patients of ter Haar et al. (1982), in whom the clinical diagnosis was made based on skeletal and craniofacial characteristics, were male, suggesting the possibility of an autosomal recessive form. These 3 original patients had additional findings of congenital glaucoma and heart defects, which were thought to be infrequent manifestations of Melnick-Needles syndrome. Hamel et al. (1995) proposed ter Haar syndrome as distinct from Melnick-Needles syndrome; recessive inheritance, congenital glaucoma, and congenital heart disease distinguish ter Haar syndrome as a unique entity. Maas et al. (2004) suggested that this disorder be referred to as Frank-ter Haar syndrome because of the initial description by Frank et al. (1973). | |||||||||||||||||||||||||||||||||
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