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Al‐Awadi/Raas‐Rothschild/Schinzel phocomelia (AARRS) syndrome, a rare autosomal recessive disorder, comprises malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. Mutations in WNT7Ahave been reported as cause of the syndrome. We report on two sisters in a Thai family with short and malformed long bones, absent fibulae, flexion contracture of digits, and a/hypoplastic nails. Fusion between severely malformed femora and slender tibiae has never been reported in patients with WNT7Amutations. Lower limbs were more severely malformed than the upper ones and the pelvis was also severely affected. Multiple fusions of long bones and of the femoral heads to the acetabula were evident. A novel homozygous missense mutation in coding exon 4 of the WNT7Awas detected in both affected daughters (c.664C > T) leading to an amino acid exchange from arginine to tryptophan (p.Arg222Trp; R222W). The phenotype is likely to result from an abnormality of all three signaling centers in the developing limb resulting in ventralization with a loss of dorsal structures (aplasia/hypoplasia of nails) a loss of anterior–posterior identity (single distal bones in lower limb without polarity) and an outgrowth defect resulting in distal truncations. © 2010 Wiley‐Liss, Inc.

Lymphedema–distichiasis syndrome is a rare primary lymphedema inherited as an autosomal dominant disorder. The characteristic features consist of late onsetlymphedema and distichiasis together with other occasionally seen features including varicose vein, cleft palate, ptosis, and congenital heart diseases. FOXC2is the gene found to be associated with this syndrome. We report here the first Thai patient who has characteristic features of this syndrome and the infrequently described features including ankyloglossia, and Robin sequence which consists of glossoptosis, cleft palate, and micrognathia. Mutation analysis of FOXC2revealed c. 595596 insC. © 2010 WileyLiss, Inc.

Dominant mutations in TP63cause ankyloblepharon ectodermal dysplasia and clefting AEC, an ectodermal dysplasia characterized by skin fragility. Since ΔNp63α is the predominantly expressed TP63 isoform in postnatal skin, we hypothesized that mutant ΔNp63α proteins are primarily responsible for skin fragility in AEC patients. We found that mutant ΔNp63α proteins expressed in AEC patients function as dominantnegative molecules, suggesting that the human AEC skin phenotype could be mimicked in mouse skin by downregulating ΔNp63α. Indeed, downregulating ΔNp63 expression in mouse epidermis caused severe skin erosions, which resembled lesions that develop in AEC patients. In both cases, lesions were characterized by suprabasal epidermal proliferation, delayed terminal differentiation, and basement membrane abnormalities. By failing to provide structural stability to the epidermis, these defects likely contribute to the observed skin fragility. The development of a mouse model for AEC will allow us to further unravel the genetic pathways that are normally regulated by ΔNp63 and that may be perturbed in AEC patients. Ultimately, these studies will not only contribute to our understanding of the molecular mechanisms that cause skin fragility in AEC patients, but may also result in the identification of targets for novel therapeutic approaches aimed at treating skin erosions. © 2009 WileyLiss, Inc.

Acro‐cardio‐facial syndrome (ACFS) is a rare autosomal recessive congenital malformation syndrome; consistent features include ectrodactyly, cleft lip/palate with minor facial anomalies, genital abnormalities, mental retardation, and growth retardation. Five cases have been reported. We report on a new patient with ACFS syndrome. In addition to the characteristic features of ACFS, the reported patient also has mild scoliosis, hemivertebrae and subclinical hyperthyroidism. These additional features may expand the phenotypic spectrum of the syndrome. © 2009 Wiley‐Liss, Inc.

We report a patient with a unique combination of features, including microcephaly; mental retardation; poorly developed frontal lobes; hypoplastic pituitary gland; hypothyroidism; alopecia universalis; single maxillary central incisor; taurodontism; median palatal ridge; longitudinally grooved nails; and scoliosis. His unbalanced karyotype was found to be 45,XY,der(15;18)(q10;q10). The constellation of anomalies appears to represent a contiguous gene syndrome caused, at least in part, by deletion of TGIF and the gene responsible for hereditary hypotrichosis simplex. The phenotype of our patient differs other reported patients with del(18p). Possible explanations include (1) the effects of a different deleted region, (2) a positional effect caused by a gene close by, or (3) by interruption of a different gene resulting from chromosomal translocation. © 2006 Wiley‐Liss, Inc.

We report a newly recognized bone disorder consisting of polyostotic expansile osteolysis affecting long bones and iliac bones; hyperostosis of the skull, thoracic cage, and medial portion of both clavicles; pectus carinatum; gigantiform synovial masses of the elbows and knees; atrial septal defect; cardiomegaly; unilateral cryptorchidism; and mental deficiency. Affected bones can be grouped into four general types of skeletal pathology: (1) expansile osteolysis, (2) osteolysis without expansion, (3) expansion without osteolysis, and (4) hyperostosis. Some bones remained unaffected. We have named the condition “polyosteolysis/hyperostosis syndrome.” It is clearly at variance with any previously reported bone disorder, including familial expansile osteolysis, juvenile Paget disease, and McCune–Albright syndrome (and polyostotic fibrous dysplasia). Because our patient shared some features in common with juvenile Paget disease, we thought that mutational analysis of TNFRSF11B was indicated, even though our patient had some manifestations not found in juvenile Paget disease. Direct sequencing failed to identify a TNFRSF11B mutation. Because the parents of our propositus were first cousins suggests that polyosteolysis/hyperostosis syndrome may possibly have autosomal recessive inheritance. © 2006 Wiley‐Liss, Inc.

We report on a 3‐year‐old Thai boy with limb, pelvic, and genital malformations. The combination of findings found in this patient is similar to that of Al‐Awadi/Raas‐Rothchild syndrome (AARRS) or limb/pelvis hypoplasia/aplasia syndrome. The upper limbs are more severely affected than the lower ones. Unlike that of AARRS, the radial ray is more severely affected than the ulnar ray. The presence of humeroulnar synostosis and humero‐ulnar‐radial synostosis and the absence of a radius distinguishes it from AARRS. The similarities and dissimilarities between the features in the present patient and other limb‐pelvic hypoplasia/aplasia syndromes are discussed. The findings in this group of patients appear to demonstrate limb‐pelvis‐genital organ developmental field defects. © 2004 Wiley‐Liss, Inc.

We report two related Thai children having a new syndrome of microcephalic osteodysplastic primordial dwarfism (MOPD). The findings which classify them as having MOPD include IUGR, microcephaly, prominent nose and nasal bridge, small pinnae, short stature, cone‐shaped and ivory‐epiphyses, delayed bone age, slender long bones, and abnormal pelvis. The findings that distinguish them as having newly recognized syndrome consist of severe microdontia, malformed teeth, single‐rooted or rootless teeth, severely hypoplastic alveolar bone, café au lait spots, acanthosis nigricans, and areas of hypo‐ and hyperpigmented skin. The reported patients appear to have the same condition as the family reported by Kantaputra [2002: Am J Med Genet 111:420–428]. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148‐7299/suppmat/index.html. © 2004 Wiley‐Liss, Inc.

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We report a Thai girl who had aglossia, micrognathia, microsomia, collapse of mandibular arch, persistence of buccopharyngeal membrane, microcephaly, and mild developmental delay. Thyroid function tests indicated that she had subclinical hypothyroidism. Thyroid scan revealed normal uptake of the whole thyroid gland. Tongue morphogenesis is integrally linked to the normal development of thyroid gland, and abnormal tongue morphogenesis could potentially result in a functional thyroid disorder. We propose that micrognathia, microsomia, congenital absence of mandibular incisors, and collapse of the mandibular arch are the result of abnormal tongue development. © 2003 Wiley-Liss, Inc.

A Thai girl with a unique combination of limb and craniofacial anomalies is reported. Manifestations include blepharoptosis; prominent nose; hypodontia; multiple, hyperplastic frenula; and dysplastic ears. Limb anomalies include short stature, postaxial polydactyly of both hands and the left foot, proximal and distal symphalangism of fingers, and congenital absence of the distal phalanges of toes 2–5. Mutation analyses of NOG and GDF5, the genes responsible for symphalangism-related syndromes, were negative. © 2003 Wiley-Liss, Inc.

A Thai man and his sister affected with a newly recognized syndrome of proportionate primordial short stature are reported. The patients had severe intrauterine and postnatal growth retardation, prominent nose and nasal bridge, small pinnae, large sella turcica, areas of hypo- and hyperpigmentation of skin, dry and thin scalp hair, and long and straight clavicles. Ivory epiphyses and cone-shaped epiphyses of the hands were found when they were young, but most of them disappeared as they grew up. Scaphoid and trapezium had angular appearance. The second toes were unusually long. Distal symphalangism of toes and barchymesophalangy of fingers were noted. The findings that appear to distinguish this syndrome from the previously reported syndromes are long second toes, opalescent and rootless teeth, severe microdontia, severely hypoplastic alveolar process, and unerupted tooth. The mode of inheritance is suspected to be autosomal recessive. © 2002 Wiley-Liss, Inc.

We report on a Thai family with dominantly inherited malformation syndrome with upper limb anomalies, short stature, quadricuspid aortic valve, and minor craniofacial anomalies. The affected individuals comprised a mildly affected mother, a moderately affected daughter, and a most severely affected son. The daughter and son had short stature. The craniofacial abnormalities comprised frontal bossing, hypoplastic nasal bones, depressed nasal bridge, and broad nasal alae. The upper limb defects varies among the patients, ranging from radial ray defects in the mother through radial and ulnar ray defects with unilateral humeral hypoplasia in the daughter to radial ray defects with severe oligodactyly and bilateral humeral hypoplasia in the son. All patients in this family had hypoplasia of the shoulder girdle and resembled what is observed in many families with Holt-Oram syndrome. Moreover, the son showed quadricuspid aortic valve with mild aortic regurgitation. However, the present family did not show any mutation of the TBX5 gene, a disease-causing gene of Holt-Oram syndrome. The present family deserves further investigation on other genes that play a role in the development of the upper limbs, particularly of radial rays. © 2002 Wiley-Liss, Inc.

A Thai mother and son with distal symphalangism and other associated abnormalities are reported. Distal and middle phalanges of fingers and toes 2–5 were either aplastic/hypoplastic or fused between the corresponding digits. The second fingers and fourth fingernails were most severely affected in both patients. The mother's hands were less severely affected; the middle and distal phalanges of her hands were malformed and fused. Besides the absence of fusion lines, the shape of the fused middle and distal phalanges was quite different from that of other types of fusion, i.e., fused bones in both patients did not maintain the normal configuration of bone, referring to as “middle-distal phalangeal complex”. Distal symphalangism was observed in toes 2–5 of the mother and in toe 3 of the son. Both patients had additional clinical manifestations such as narrowing of the zygomatic arch, dental pulp stone, microdontia of a mandibular permanent central incisor, cone-shaped epiphyses of middle phalanges of fingers, and absence of scaphoid, trapezium, trapezoid, and pisiform bones. Mutation analysis of NOG and ROR2, the genes responsible for proximal symphalangism and brachydactyly type B, respectively, was negative. © 2002 Wiley-Liss, Inc.

A four-generation Thai family affected with Van der Woude syndrome is reported. The disorder appeared to be originally inherited from a person who was half Thai and half Pakistani. The lip lesions found in this family were varied and did not appear to be related to other phenotypes. There were some clinical manifestations possibly specific for the condition in this family. They included sensorineural hearing loss, prominent frontal bone, large frontal/sphenoidal/maxillary sinuses with increased mastoid air cells, long tooth roots, dental pulp stones, ankyloglossia, brachydactyly of hands, brachyphalangy, and hyperphalangy of toes, and single flexion crease of the fifth fingers. Fluorescence in situ hybridization analysis revealed no visible deletion at a 1q32-41 region. © 2002 Wiley-Liss, Inc.

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We report two daughters of a Thai family affected with mental retardation, delayed speech, obesity, craniofacial manifestations, and ocular anomalies. Craniofacial manifestations included macrocephaly, maxillary hypoplasia, mandibular prognathism, and crowding of teeth. Ocular anomalies consisted of blepharophimosis, blepharoptosis, decreased visual acuity, abducens palsy, hyperopic astigmatism, and accommodative esotropia. Chronic atopic dermatitis, lateral deviation of the great toes, and cone-shaped epiphyses of the toes were observed. The disorder is suggested to be autosomal recessive. The combination of findings found in our patients has not hitherto been described. © 2001 Wiley-Liss, Inc.

We report on an 8-year-old Thai girl with bilateral complete cryptophthalmos, facial asymmetry, delayed bone age, brachymesophalangy and medial deviation of the second toes, and dental anomalies. The dental anomalies consist of delayed dental development, congenital absence of the second premolars, microdontia of the deciduous molars. A fibrous band of the buccal mucosa was found. Dental anomalies are rare among patients with Fraser syndrome. They have not been reported in either isolated or other syndromic cryptophthalmos. The oral manifestations and brachymesophalangy of the second toes found in our patient may represent newly recognized findings associated with cryptophthalmos or they may represent a newly recognized syndrome. © 2001 Wiley-Liss, Inc.

A Thai man with Laurin-Sandrow syndrome (LSS, MIM 135750), the ninth reported case, is described. He had an underdeveloped nasal bone, scar-like seams under the nose, large heads of mandibular condyles, and brachymesophalangy of toes as newly observed findings of the syndrome. He also had mental retardation. The patient had duplication of ulna, with triphalangeal thumbs, and polydactyly of one finger. The triphalangeal thumbs were non-opposable. Carpal bones were malformed. Mirror image polydactyly of the toes was present. There were nine toes on the right and eight on the left. Joint abnormalities were observed at his elbows, wrists, knees, ankles, fingers, and toes. Synostosis of severely malformed tarsal bones was noted. This appears to be the first case of LSS with anomalies not limited to the nose and limbs. The relationship between LSS, tibial hemimelia-polysyndactyly-triphalangeal thumbs syndro- me, triphalangeal thumb-polysyndactyly syndrome, preaxial polydactyly types 2 and 3, and Haas-type syndactyly is discussed. © 2001 Wiley-Liss, Inc.

We report on a Thai man who had triphalangeal thumb-polysyndactyly syndrome (TPTPS, MIM *190605) and his daughter who had tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS, MIM *188770). The father had polysyndactyly of triphalangeal thumbs, syndactyly of fingers, duplicated distal phalanx of the left great toe, brachymesophalangy of toes, and the absence of middle phalanges of some toes. He was diagnosed as having TPTPS. His daughter was more severely affected, having complete syndactyly of five-fingered hands in rosebud fashion (Haas-type syndactyly), hypoplastic tibiae, absent patellae, thick and displaced fibulae, preaxial polysyndactyly of triphalangeal toes, and cutaneous syndactyly of some toes, the manifestations being consistent with THPTTS. Having two different syndromes in the same family suggests that they are actually the same disorder. A literature survey showed that there have been several families where THPTTS occurred with TPTPS or Haas-type syndactyly (and/or preaxial polydactyly type 2, PPD2). In addition, all loci for TPTPS, THPTTS, and PPD2 (and/or PPD3) have been assigned to chromosome band 7q36. These findings support our conclusion that TPTPS, PPD2 (and/or PPD3), and Haas-type syndactyly are a single genetic en-tity (THPTTS). We propose to call the condition “tibial hemimelia-polysyndactyly-triphalangeal thumbs syndrome.” Am. J. Med. Genet. 93:126–131, 2000. © 2000 Wiley-Liss, Inc.

The cases of two patients with Robinow fetal face syndrome, an 11-year-old Thai boy and a newborn Caucasian girl, are described. The Thai boy had the characteristics typical of the dominant type of the syndrome with a few newly recognized signs, including communicating hydrocephalus, underdeveloped sinuses, short roots of the teeth, narrow and thick-floored pulp chambers, hypoplastic nipples, absent middle phalanges of the second to fifth toes, cone-shaped epiphyses of the second and fourth fingers and fifth toes, single creases of the fourth and fifth fingers, clinodactyly of the third fingers, dysmorphic umbilicus, and shawl scrotum. The girl had anomalies typical of the recessive type of the syndrome. She also had capillary hemangioma at the tip of her nose and hypoplastic fourth metatarsal bones, which are the newly recognized features of the recessive type. Infrequently reported clinical manifestations of the syndrome are discussed. Am. J. Med. Genet. 84:1–7, 1999. © 1999 Wiley-Liss, Inc.

We report on a boy with Rapp-Hodgkin syndrome (RHS) or Rapp-Hodgkin ectodermal dysplasia. He had sparse, wiry, slow growing and uncombable hair, but no pili torti or pili canaliculi characteristic of RHS. He also had sparse eyelashes and eyebrows, and obstructed lacrimal puncta and epiphora. Bilateral bony external auditory canal stenosis led to hearing loss. The mouth was small with repaired bilateral cleft lip and palate. Oral manifestations included hypodontia, microdontia, unerupted mandibular premolars with well formed roots, large dental pulp spaces, enamel hypoplasia, multiple caries, glossy tongue, and congenital absence of lingual frenum and of sublingual caruncles including submandibular and sublingual salivary duct openings. Palmoplantar keratoderma, unerupted premolars, congenital absence of lingual frenum, sublingual caruncles, glossy tongue, and pili canaliculi seen in the patient are newly recognized findings of this syndrome. Overlapping findings of RHS ectrodactyly–ectodermal dysplasia–clefting syndrome (EEC), and ankyloblepharon–ectodermal defects–cleft lip and palate syndrome (AEC) are discussed. Am. J. Med. Genet 79:343–346, 1998. © 1998 Wiley-Liss, Inc.

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