OBJECTIVE: Poland syndrome is a rare congenital anomaly characterized by complete or partial agenesis of the pectoralis major muscle variably associated with other thoracic malformations, upper limb malformations, or both. More than 20 patients with dextrocardia and left-sided Poland syndrome have been previously described. The association between these 2 rare anomalies suggests a causal relationship, but the etiopathogenetic mechanism has not been clarified yet. We studied the clinical correlation between these 2 anomalies, and we tried to elucidate whether dextrocardia or Poland syndrome comes first. METHODS: This is a multicentric multidisciplinary study conducted over the last 5 years. We identified 122 patients with Poland syndrome, and we investigated heart position through different imaging techniques. Logistic regression statistical analyses were carried out. RESULTS: We observed dextrocardia in 14 (11.5%) patients, which was never associated with situs inversus. All of them presented with left-sided Poland syndrome and partial agenesis of 2 or more ribs. Conversely, all patients with Poland syndrome with partial agenesis of 2 or more ribs presented with dextrocardia, whereas dextrocardia was never associated with partial agenesis of a single rib. Three patients with dextrocardia presented with simple congenital heart defects. CONCLUSIONS: These findings suggest that mechanical factors during embryonic life could explain the strong association between left-sided Poland syndrome and dextrocardia. According to this hypothesis, partial agenesis of 2 or more ribs is needed to displace the heart toward the right side. The peculiar features of dextrocardia when associated with Poland syndrome (neither associated with situs inversus nor complex intracardiac anomalies) support our hypothesis.

ABSTRACT: BACKGROUND: Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) consists of congenital aplasia of the uterus and the upper part of vagina due to anomalous development of Mullerian ducts, either isolated or associated with other congenital malformations, including renal, skeletal, hearing and heart defects. This disorder has an incidence of approximately 1 in 4500 newborn girls and the aetiology is poorly understood. Methods and Results: we report on two patients affected by MRKH syndrome in which array-CGH analysis disclosed an identical deletion spanning 1.5 Mb of genomic DNA at chromosome 17q12. One patient was affected by complete absence of uterus and vagina, with bilaterally normal ovaries, while the other displayed agenesis of the upper part of vagina, right unicornuate uterus, non cavitating rudimentary left horn and bilaterally multicystic kidneys. The deletion encompassed two candidate genes, TCF2 and LHX1. Mutational screening of these genes in a selected group of 20 MRKH females without 17q12 deletion was negative. CONCLUSION: Deletion 17q12 is a rare albeit recurrent anomaly mediated by segmental duplications, previously reported in subjects with developmental kidney abnormalities and diabetes. The present two patients expand the clinical spectrum associated with this imbalance and suggest that this region is a candidate locus for a subset of MRKH syndrome individuals, with or without renal defects.

Poland syndrome (PS) has been described as unilateral pectoral muscle deficiency variably associated with ipsilateral thoracic and upper limb anomalies. Bilateral hypoplasia/aplasia of the pectoralis muscle and upper limb defects in association with variable thoracic muscles, chest wall deformities and lower limb defects have been infrequently reported in the literature. We report on a 3(1/2)-year-old girl with clinical features consisting in bilateral asymmetric pectoral muscle defects (complete agenesis on the left side and agenesis of the sternocostal head on the right side), nipple hypoplasia, left rib defect, and right hand symbrachydactyly. In this study, we reviewed the bilateral features present in our patient and those described in the literature. Hypotheses explaining bilateral features in PS are reviewed.(c) 2009 Wiley-Liss, Inc.

We report on clinical and molecular findings of two brothers that both presented with sagittal craniosynostosis, hydrocephalus, Chiari I malformation, blepharophimosis, small low-set ears, hypoplastic philtrum, radioulnar synostosis, kidney malformation, and hypogenitalism. Their father presented mild brachydactyly. Conventional cytogenetic and array CGH screening did not show any chromosomal gains or losses. Furthermore, molecular genetic screening of genes involved in different craniosynostosis syndromes, namely FGFR1, FGFR2, FGFR3, TWIST, RECQL4, and POR genes failed to detect any mutations in genomic DNA. The unique range of clinical manifestations in these two patients and the negative findings of the molecular genetic screening suggest the hypothesis of a previously unrecognized syndrome.

Longitudinal bone growth is determined by the process of endochondral ossification in the cartilaginous growth plate, which is located at both ends of vertebrae and long bones and involves many systemic hormones and local regulators. We report the molecular characterization of a de novo balanced t(2;7)(q37.1;q21.3) translocation in a young female with Marfanoid habitus and skeletal anomalies. The translocation was characterized by fluorescence in situ hybridization (FISH), checked for other abnormalities by array-comparative genomic hybridization (CGH), and finally, the breakpoints were cloned, sequenced, and compared. Biochemical dosage was applied to study the possible mechanisms that may cause the proposita's phenotype. The breakpoint on chromosome 2 disrupts the hypothetical gene MGC42174 (HUGO-approved symbol DIS3L2) and is located in the proximity of the NPPC gene coding for C-type natriuretic peptide (CNP), a molecule that regulates endochondral bone growth. CNP plasma concentration was doubled in the proband compared to five normal controls, while NPPC was substantially overexpressed in her fibroblasts. A transgenic mouse generated to target NPPC overexpression in bone showed a phenotype highly reminiscent of the patient's phenotype. The breakpoint on chromosome 7 is localized proximally at about 75 kb from the COL1A2 gene. The COL1A2 allele on the derivative chromosome was strongly underexpressed in fibroblasts, but total collagen was not significantly different from controls. Several evidences support the conclusion that the proband's abnormal phenotype is associated with C-type natriuretic peptide overexpression. Hum Mutat 0, 1-8, 2007.(c) 2007 Wiley-Liss, Inc.

Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by absence of automatic control of respiration, decreased sensibility to hypoxia and hypercapnia mainly during sleep, and autosomal dominant inheritance due to heterozygous polyalanine expansions and frameshift mutations in the PHOX2B gene. Because the congenital central hypoventilation syndrome phenotype could hide other neurological diseases, the American Thoracic Society established that the initial evaluation of suspected Congenital Central Hypoventilation Syndrome should exclude neuro-anatomic impairments as the structural basis of the reduced autonomic system function. In this work, we describe the clinical history of two unrelated patients with hypoventilation during sleep and harboring hypoplasia of the pons and a Chiari I malformation, respectively. In both patients, congenital central hypoventilation syndrome was diagnosed by detection of PHOX2B polyalanine expansion, suggesting that the American Thoracic Society diagnostic criteria may be too restrictive. Moreover, in order to exclude a putative role of PHOX2B in non-CCHS neurological diseases, we have performed PHOX2B mutation screening in a group of individuals with Chiari I malformation, confirming the exclusive role of PHOX2B in the pathogenesis of Congenital Central Hypoventilation Syndrome.

BACKGROUND: In hyperthyroidism-complicated pregnancies, medical therapy is necessary to reach an euthyroid condition, and propylthiouracil (PTU) or methimazole (MMI) are used. These drugs are equally effective, but may cause fetal and neonatal hypothyroidism because they freely cross the placenta. Although PTU has not been significantly associated with embryo-fetal anomalies, it has been suggested that MMI might be responsible for a specific embryopathy. CASE(S): Two cases of major congenital anomalies after MMI exposure during pregnancy are reported. CONCLUSIONS: PTU should be the drug of choice, and the use of MMI should be restricted to cases with allergic reactions, intolerance, or poor response to PTU. Birth Defects Research (Part A), 2003.

PURPOSE: Axenfeld-Rieger syndrome is an ocular anterior segment dysgenesis, autosomal dominantly inherited, commonly associated with glaucoma and systemic anomalies. This study presents various clinical manifestations of Axenfeld-Rieger syndrome within one family. MATERIAL AND METHODS: Three members of the family: patient 1--father (54 years old), patient 2--son (31 years old), and patient 3--daughter (30 years old), underwent complete ophthalmic examination, including standard glaucoma diagnostics. Additional investigations, such as: ultrasound biomicroscopy (UBM, Opticon 2000), corneal topography Orbscan II (Bausch & Lomb, Inc., Rochester, N.Y., USA), corneal confocal microscopy ConfoScan 3 (Nidek Technologies), central corneal thickness measurements with optical low-coherence reflectometer (OLCR, pachymeter Haag-Streit), were carried out. It was impossible to perform complete eye examination in one case (patient 1) because of severity of ocular changes. RESULTS: All family members described had iris abnormalities (hypoplastic iris stroma) and early-onset glaucoma, however severity of symptoms were different in each case. The most advanced disease was recognized in patient 1. Other findings included: posterior embryotoxon (patients 2 and 3), iridocorneal angle abnormalities (patients 2 and 3), microcornea (patient 2) and extraocular features (patients 1 and 2): dental anomalies (microdontia and hypodontia), maxillary hypoplasia and periumbilical skin fold. All of these symptoms supported the diagnosis of Axenfeld-Rieger syndrome. In addition, we also diagnosed keratoconus in patient 2 and hypermetropia, strabismus and corneal scar in patient 3. CONCLUSIONS: Reported cases of Axenfeld-Rieger syndrome demonstrate phenotypic variability of the disease among family members, which is characteristic for this disorder and can cause diagnostic problems.

ARC syndrome, the association of arthrogryposis, renal tubular dysfunction and cholestasis, is a rare genetic disorder. We report two Saudi infants from two different families with ARC syndrome. Magnetic resonance imaging of the brain of one of the infants showed lissencephaly, a previously unreported finding in this syndrome. We also review 39 ARC cases reported in the literature using the Medline database from January 1966 to September 2004.

Michelin tire syndrome is a rare syndrome characterized by excessive folding of the skin. The diagnosis is mainly clinical. It has been found to be associated with noncutaneous anomalies, and probably reflects multiple underlying disorders. We report two siblings with Michelin tire syndrome, a 5-year-old boy and his sister both of whom had marked skin folds and facial anomalies. Histologic study found an increase in smooth muscle fibers of the dermis. Electron microscopy showed details of smooth muscle cells. We also review reported cases in the literature to contribute to a better understanding of this syndrome.

Fraser syndrome is a rare genetic syndrome with abnormalities of the head, lungs, kidneys, and limbs. A prenatal diagnosis of FS can be done in families with risk, using foetal ultrasonography. However, a wide qualitative and quantitative variability of possible abnormalities makes the diagnosis in utero notably questionable. We present the results of foetal ultrasonography in a tertigravida, had delivered two children with FS. Signs of foetal hypertelorism and microphthalmia, both traits typical for FS, were detected based on outer and inner orbital diameters and ocular diameters in 28 and 32 weeks of pregnancy. The clinical and pathological examinations after birth confirmed the diagnosis of FS. Our observation suggests that eye anomalies may prompt the diagnosis of FS even if characteristic lung and kidney abnormalities are absent. Therefore, we propose to regularly assess eye dimensions and distance, when performing any foetal ultrasonography in families with of FS.

We describe two cases of oculocerebrocutaneous syndrome (OCCS) or Delleman syndrome, characterized by congenital anomalies that involve the skin, orbit, and central nervous system (CNS). Complete MRI studies of the orbit, CNS and the entire spinal region must be performed in these cases. New MRI techniques can show cortical malformations, such as polymicrogyria, lissencephaly, or abnormal disposition of cortical sulci and gyri. Lesions can be bilateral or unilateral, as occurred in our patients. In one case, the ocular, skin, cerebral, and cerebellar lesions involved mainly the same side, whereas in the second case, all anomalies were generalized and the patient also showed skin hypopigmented lesions distributed bilaterally. Both patients show severe encephalopathy and Dandy-Walker malformation. One case is blind and shows generalized hydrocephalus, and the other one has vision through an eye, and has complete agenesis of the corpus callosum and severe disorder of neuronal migration and cortical organization with polymicrogyria and abnormal cortical sulci and gyri in a cerebral hemisphere. Our second case shows arachnoid cysts in both temporal, retrocerebellar, and spinal (D(8)-D(11)) regions, and lipoma in the pontomedullary and spinal (D(4)-D(7)) regions. The latter features correspond more to ECCL than to OCCS. The overlap between the two syndromes is unquestionable and it is possible that they constitute different manifestations of the same disorder.

We describe a newborn infant with defects similar to those seen in mice heterozygous for the mutant disorganization (Ds) gene. The child had left popliteal webbing, left iliac bone hypoplasia, bifid scrotum, hypospadias, chordee deformity of the penis and a sacral dimple. Other anomalies included absence of the right kidney and a bizarre hamartomatous tubular skin pedicle on the left thigh. No obvious amniotic bands or oligohydramnios were noted. The similarity between the proband's anomalies, those in previously reported cases, and those found in mice support the possibility of a human homologue of the Ds gene.

We report a 6 month old boy with congenital hydronephrosis, cleft palate, severe hypotonia, congenital heart defect, developmental delay, and characteristic facial features with an open mouthed appearance and full lower lip, who we believe is the third reported case of Okamoto syndrome. Okamoto syndrome is a recently described distinctive multiple congenital anomaly syndrome encompassing the above features for which an etiologic factor has not yet been identified. Our patient also had idiopathic splenomegaly and non-specific MRI changes in the brain, not reported in the first two cases.