Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia.

We present an autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this clinical entity to chromosome 12q21. In one of the families, three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene, which encodes the aristaless-like homeobox 1 transcription factor. In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. Unlike loss of its murine ortholog, loss of human ALX1 does not result in neural-tube defects; however, it does severely affect the orchestrated fusion between frontonasal, nasomedial, nasolateral, and maxillary processes during early-stage embryogenesis. This study further expands the spectrum of the recently recognized autosomal-recessive ALX-related FND phenotype in humans.

Prenatally diagnosed case of 22q11.2 deletion syndrome associated with pulmonary artery aneurysm.

Here, we report a new case with chromosome 22q11 deletion and cardiac anomaly diagnosed prenatally by echocardiography. Fluorescence in situ hybridization (FISH) analysis demonstrated a heterozygous deletion at 22q11.2. Echocardiography revealed ventricular septal defect, pulmonary atresia, and aneurysm of the main pulmonary artery and its branches. Pulmonary artery aneurysm (PAA) is rarely seen in patients with 22q11.2 deletion syndrome (22qDS). In this case, PAA was found by prenatal echocardiographic examination at the 25th week of gestation. To date, no prenatally diagnosed case of 22qDS with PAA has been reported. This is the first 22qDS case with PAA that was detected prenatally by FISH analysis.

ALX4 dysfunction disrupts craniofacial and epidermal development.

Genetic control of craniofacial morphogenesis requires a complex interaction of numerous genes encoding factors essential for patterning and differentiation. We present two Turkish families with a new autosomal recessive frontofacial dysostosis syndrome characterized by total alopecia, a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, hypogonadism, callosal body agenesis and mental retardation. Using homozygosity mapping, we mapped the entity to chromosome 11p11.2-q12.3 and subsequently identified a homozygous c.793C-->T nonsense mutation in the human ortholog of the mouse aristaless-like homeobox 4 (ALX4) gene. This mutation is predicted to result in a premature stop codon (p.R265X) of ALX4 truncating 146 amino acids of the protein including a part of the highly conserved homeodomain and the C-terminal paired tail domain. Although the RNA is stable and not degraded by nonsense-mediated RNA decay, the mutant protein is likely to be non-functional. In a skin biopsy of an affected individual, we observed a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation. Our data indicate that ALX4 plays a critical role both in craniofacial development as in skin and hair follicle development in human.

Familial ring (18) mosaicism in a 23-year-old young adult with 46,XY,r(18) (::p11→q21::)/46,XY karyotype, intellectual disability, motor retardation and single maxillary incisor and in his phenotypically normal mother, karyotype 47,XX,+r(18)(::p11→q21::)/46,XX.

We report on a 23-year-old man with craniofacial findings of the holoprosencephaly spectrum disorder (microcephaly, hypotelorism, depressed nasal bridge, single median maxillary central incisor), fusion of C2-C3 vertebrae, intellectual disability, and severe sleep apnea. Chromosome analysis of blood lymphocytes showed 75% ring (18) cells and 25% normal cells, karyotype mos 46,XY,r(18)(::p11→q21::)[75]/46,XY[25]. His mother was phenotypically normal except for a double ureter and bifid renal pelvis as in his son. She had a supernumerary ring (18) in 10% of blood lymphocytes, karyotype mos 47,XX,+r(18)(::p11→q21::)[10]/46,XX[90]. Familial ring (18) is a rare cytogenetic abnormality. This is the first report of a mother with a supernumerary ring (18) and a son with ring (18) mosaicism. Interestingly, the son showed a true mosaicism (mixoploidy) of ring (18) and normal cells. The mother's 46,XX cells could be easily explained by mitotic instability and ring loss during cell division. However, the coexistence of ring (18) and normal cells in the son is unusual. Possibly, during early postzygotic divisions of a 47,XY,+r(18) zygote, two (possibly subsequent) genetic events could have occurred, one when one normal chromosome 18 was lost (resulting in a cell line with ring 18), and one when the ring 18 was lost (resulting in a cell line without ring, "escape to normal"). Alternatively, the zygote of the son could have been 46,XY,r(18), and postzygotic loss of the ring 18 could have resulted in monosomy 18 cells followed by duplication of chromosome 18 in these cells (a rare mechanism for cell survival previously described as "compensatory" isodisomy).

A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb.

Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the "Cuban mutation" of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb-polysyndactyly syndrome, but do not affect lower limb development. We suggest the term "ZRS-associated syndromes" and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS.

Characterization of double ring chromosome 4 mosaicism associated with bilateral hip dislocation, cortical dysgenesis, and epilepsy.

We present the clinical and molecular findings in a Turkish child with a de novo mosaic ring derived from chromosome 4 with multiple cell-lines; the karyotype was 46,XY,r(4)[83]/45,XY, -4[6]/47,XY,r(4),+r(4)[5]/48,XY,r(4),+r(4),+dic r(4)[1]/46,XY[5]. The patient is a 20-month-old male who was the first pregnancy of nonconsanguineous parents. The baby was delivered at term with a birth weight of 1,700 g (<3rd centile) and a length of 46 cm. The baby had feeding difficulties and vomiting problems. He started walking at age 2 years and delayed language was observed. Facial appearance was normal, but the ears were large with abnormal structure. The hands showed bilateral clinodactyly of the 5th fingers. He had mild mental retardation, and epilepsy. Analysis of chromosomes showed 46,XY,r(4)(::p16.3 --> qter::)[67]/46,XY,r(4;4)(::p16.3 --> qter::p16.3 --> qter::)[2]/46,XY[3] by multicolor banding (MCB) technique. Array CGH delineated the size of the terminal deletion as 900 kb in 4p16.3. The Wolf-Hirschhorn critical region was preserved even though our patient had mild mental and motor retardation. While the mosaicism of the ring 4 could affect the phenotype, the deleted 900 kb distal deletion and clinical features of the patient may provide further insight into characteristic phenotype of the 4p- related syndromes.

Approach in an adolescent Proteus male patient with megafoot.

Proteus syndrome is a rare overgrowth syndrome characterized by hemihypertrophy, lower limb asymmetry, hyperpigmentations, lipomas, and vascular malformation. In this paper, we present a new adolescent Proteus syndrome patient with bilateral megafoot. He was very successful in playing football and was very popular among his friends. We present this case for the psychological and surgical aspects of this very interesting entity. We also review the recent literature related with Proteus syndrome.

A well-documented trisomy 13 case presenting with a number of common and uncommon features of the syndrome.

Trisomy 13 is a very rare and lethal autosomal chromosomal malformation syndrome. Its incidence is 1/12,000 births. In this paper, we present a new trisomy 13 case associated with unusual and undescribed findings. This patient was the first child of unrelated parents with advanced maternal and paternal age, at 36 and 38 years, respectively. Unfortunately, the parents did not accept the prenatal diagnosis. The baby was born after 34 weeks of gestation by cesarian section. His birth weight was 1,865 g and he demonstrated typical craniofacial abnormalities for trisomy 13 such as severe microphthalmia, microcephaly and scalp defects, and peripheral chromosome analysis revealed trisomy 13. He died of congenital heart disease and sepsis on the 12th hospital day. A complete autopsy revealed a scalp and a skull defect at the vertex, aplasia of the 5th finger nails, a complex heart disease including pulmonary trunk atresia, patent foramen ovale, membranous ventricular septal defect (VSD), main aorticopulmonary collateral artery (MAPCA) and aortic dextroposition, arrhinencephaly, partial agenesis of the corpus callosum, and neuronal heterotopias in the cerebellum. He also had bilateral cystic renal dysplasia, Meckel's diverticulum, right inguinal hernia, ectopic splenic tissue in the pancreas, and ectopic thymus tissue adjacent to the thyroid. To our knowledge, this is a unique trisomy 13 case with numerous common and uncommon features including a bone defect in the skull, partial agenesis of the corpus callosum, aplasia of the 5th finger nails, and a complex heart disease including pulmonary atresia, patent foramen ovale, membranous VSD, MAPCA and aortic dextroposition, which have not been published previously in the relevant literature all together.

Rubinstein-Taybi syndrome with normal FISH result and CREBBP gene analysis: a case report.

We report on a six-year-old boy with typical Rubinstein-Taybi syndrome (RSTS) phenotype. Clinical findings included mental and motor retardation, patent ductus arteriosus (PDA), undescended testes, hirsutism, broad thumbs with radial angulation and broad toes, and inguinal hernia. His karyotype was normal (46, XY) and fluorescence in situ hybridization (FISH) showed no deletion of the CREBBP [cAMP response element-binding (CREB) binding protein] gene on chromosome 16p13.3. CREBBP gene sequencing also revealed normal results. We wish to present this case because this patient had typical RSTS phenotype, but normal FISH and CREBBP gene sequencing results. It could be possible that genetic heterogeneity is related with novel mutations in other genes. With the publication of such cases, their significance will be brought to the attention of researchers in this field.

Prenatally diagnosed lethal type Larsen-like syndrome associated with bifid tongue.

Larsen syndrome is characterized by multiple joint dislocations, associated with a typical facial appearance and frequently other abnormalities. Both dominant and recessive patterns of inheritance have been reported. A lethal form of Larsen syndrome (Larsen-like syndrome) has been described as a combination of the Larsen phenotype and pulmonary hypoplasia. In this report, we present a 24-week-old female fetus with a possible prenatal diagnosis of thanatophoric dysplasia in whom postmortem examination revealed lethal type Larsen-like syndrome associated with bifid tongue, severe micrognathia and non-immune hydrops fetalis. These findings have not been reported previously in the lethal type Larsen syndrome.

Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel-Gruber syndrome.

Meckel-Gruber syndrome (MKS) is an autosomal recessive, usually lethal multisystemic disorder characterized by early developmental anomalies of the central nervous system, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Three MKS loci have been mapped and recently, two genes were identified: MKS1 on 17q22 in Caucasian kindreds and MKS3 on 8q22 in Omani and Pakistani families, putting MKS on the growing list of ciliary disorders ("ciliopathies"). We performed linkage analysis for MKS1-3 in 14 consanguineous and/or multiplex families of different ethnic origins with histologic diagnosis and at least three classic MKS manifestations in each kindred. Unexpectedly, only five families were linked to any of the known MKS loci, clearly indicating further locus heterogeneity. All five families showed homozygosity for MKS1 and, intriguingly, were of non-Caucasian origin. MKS1 sequencing revealed no mutation in two of these pedigrees, whereas different, novel splicing defects were identified in the three other families and an additional sporadic German patient. Given that all of our mutations and two of the in total four known MKS1 changes cause aberrant splicing (while the other two known mutations were frameshift mutations), we hypothesize that splicing defects are a crucial mutational mechanism in MKS1 which apparently is one of the main loci and key players in MKS. Our results indicate that MKS1 mutations are not restricted to the Caucasian gene pool and suggest further genetic heterogeneity for MKS. Overall, our data have immediate implications for genetic counselling and testing approaches in MKS.

Effective treatment of multifocal aggressive fibromatosis with low-dose chemotherapy.

Desmoid tumor (aggressive fibromatosis), as a member of a group of borderline neoplasms, is a rare tumor of fibroblastic origin that remains difficult to treat. Treatments with surgery, radiotherapy and different medical protocols including interferon (IFN)-alpha, hormonal agents such as tamoxifen (anti-estrogen) as well as non-steroidal anti-inflammatory drugs and low-dose antineoplastic agents have been reported. In this report we describe a new patient with multifocal aggressive fibromatosis who was successfully treated with low-dose chemotherapy consisting of methotrexate and vinblastine.

A 13-year-old female with Turner syndrome and achalasia.

The most common gastrointestinal problems associated with Turner syndrome are intestinal telangiectasia, colon carcinomas, inflammatory bowel, and liver diseases. In this paper we present for the first time a 13-year-old female with 45,X karyotype associated with achalasia. As far as we know, achalasia associated with Turner syndrome has not been reported previously. The aim of this report was to point out the association of Turner syndrome and achalasia. It could be a coincidental or Turner syndrome-associated finding.

Mandibuloacral dysplasia and LMNA A529V mutation in Turkish patients with severe skeletal changes and absent breast development.

Mandibuloacral dysplasia (MAD) is an autosomal recessive disorder characterized by acroosteolysis (resorption of terminal phalanges), skin changes (hyperpigmentation), clavicular hypoplasia, craniofascial anomalies, a hook nose and prominent eyes, delayed closures of the cranial sutures, lipodystrophy, alopecia, and skeletal anomalies. MAD patients are classified according to lipodystrophy patterns: type A and type B. The vast majority of MAD cases are caused by LMNA gene mutations. MAD patients with type A lipodystrophy (MADA) have been reported to have LMNA R527H, A529V, or A529T mutations. In this report, we describe two MADA patients with progressive skeletal changes, absent breast development, and cataract in addition to the classical MAD phenotype. Both patients were found to be homozygous for the Ala529Val mutation of the LMNA gene. Our female patient is the oldest MADA patient (59 years old) who has ever been reported with the LMNA mutation and also the LMNA Ala529Val mutation. This study is the second report on MADA patients with a homozygous Ala529Val mutation.

A new case of omphalocele with absence of thumb.

Omphalocele, or exomphalos, is a rare defect of the periumbilical abdominal wall in which the coelomic cavity is covered with peritoneum only, resulting in congenital eventration of abdominal contents at the base of the umbilical cord. The etiology is still unknown. In this paper a new case of omphalocele with absence of the right thumb in a five-year-old boy is reported. A common etiology and a new terminology for this combination are suggested.

An anencephalic monocephalus diprosopus "headed twin": postmortem and CT findings with emphasis on the cranial bones.

Monocephalus diprosopus is a form of conjoined twinning characterized by a single body, one unusual head and two faces or a spectrum of duplication of the craniofacial structures. Such cases have been mainly described according to postmortem pathologic examination. This presented case is a 26-week-stillborn female fetus, with unusual facial appearance with four eyes, two mouths, two noses, two ears and a defective cranial vault. To our knowledge, a detailed computerized tomography (CT) examination of the aberrant facial and cranial bones of such a case has not been reported to date. In this reported case, we present an anencephalic monocephalus diprosopus "headed twin", and describe the CT findings with emphasis on the cranial bones.