Maternal medium-chain acyl-CoA dehydrogenase deficiency identified by newborn screening.

Prior to the advent of expanded newborn screening, sudden and unexplained death was often the first and only symptom of medium-chain acyl-CoA dehydrogenase deficiency (MCADD). With the use of tandem mass spectrometry, infants can now be identified and treated before a life threatening metabolic decompensation occurs. Newborn screening has also been shown to detect previously undiagnosed maternal inborn errors of metabolism. We have now diagnosed two women with MCADD following the identification of low free carnitine in their newborns. While one of the women reported prior symptoms of fasting intolerance, neither had a history of metabolic decompensation or other symptoms consistent with a fatty acid oxidation disorder. These cases illustrate the importance of including urine organic acid analysis and an acylcarnitine profile as part of the confirmatory testing algorithm for mothers when low free carnitine is identified in their infants.

Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3.

A unique type of craniofacial dysostosis, Crouzon syndrome with acanthosis nigricans (CAN), has been attributed to a specific substitution (Ala391Glu) in the fibroblast growth factor receptor 3 (FGFR3) gene. At birth, individuals with this disorder have craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia, hydrocephalus, and they experience the onset of acanthosis nigricans during childhood. We report three cases and compare the clinical characteristics of our cases with the previously reported cases of this disorder. Since the Ala391Glu substitution in FGFR3 is close to the substitutions in the transmembrane domain that result in achondroplasia, we carefully reviewed the skeletal findings in six patients. We identified subtle radiographic findings of achondroplasia in all six cases including narrow sacrosciatic notches, short vertebral bodies, lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally, and broad, short metacarpals and phalanges. Even before acanthosis nigricans appears, the presence of choanal atresia and hydrocephalus in an individual with features of Crouzon syndrome should suggest the diagnosis of CAN, and subtle skeletal findings can lend further support to this diagnosis.

"Baby rattle" pelvis dysplasia.

We report an apparently previously undescribed lethal skeletal dysplasia, clinically resembling achondrogenesis, but with distinct radiologic and chondro-osseous morphologic features. These comprise bifid distal ends of the long bones of the limbs, absent vertebral body ossification, a unique "baby rattle" pelvic configuration with tall and broad ilia, absent endochondral ossification, regions of mesenchymal cells within the resting cartilage, and abnormal mesenchymal ossification.

Frontonasal malformation and cloacal exstrophy: a previously unreported association.

We report on a child with frontonasal malformation (FNM) and cloacal exstrophy, a combination of findings that have not been reported previously. In FNM and cloacal exstrophy, associated malformations are rare. FNM and cloacal exstrophy both represent abnormalities of the development of the midline field; this combination of anomalies in this patient suggests an impairment of caudal and cranial midline development during blastogenesis.

Complete nasal agenesis with bilateral microphthalmia and unilateral duplication of the thumb.

Complete nasal aplasia is an extremely rare clinical entity and most infants are stillborn when this is associated with holoprosencephaly. A viable 3-year-old infant born with frontonasal arrest without holoprosencephaly is presented. The child's main complaint was lack of a nasal airway, which made eating extremely difficult. A method for craniofacial reconstruction of the nasopharynx is presented.

Midline defects of the orofaciodigital syndrome type VI (Váradi syndrome).

The orofaciodigital syndromes (OFDS) represent a spectrum of anomalies of the palate, cranium, hands, and feet. Váradi syndrome, designated OFDS type VI, is a rare disorder that is additionally characterized by cerebellar anomalies. The following report is of a patient with OFDS VI and characteristic multiple midline defects: median cleft lip and palate, lingual cleft with nodules, and midline brain malformation. In addition, this case is uniquely associated with the presence of midline (metopic and sagittal) craniosynostoses as well. It is unusual that deformities which result from premature fusion of cranial vault sutures would appear synchronously in a syndrome based on the concept of failure of fusion or coalescence of facial growth centers. The midline represents an independent developmental field, whereby CNS defects and midline anomalies can present concurrently.

The association of cleft lip and palate with Aicardi syndrome.

In summary, Aicardi syndrome is defined by its tetrad of infantile spasms, agenesis of the corpus callosum, mental retardation, and chorioretinal lacunae. We report a case of Aicardi syndrome with associated cleft lip and palate. This is an infrequent finding that is present in approximately 3 percent of reported cases. Plastic surgeons should be aware of this association when treating patients with cleft lip and palate.

Should all pregnant patients be offered prenatal diagnosis regardless of age?

OBJECTIVE: To assess the acceptance of prenatal genetic diagnosis by patients younger than 35 years old who are therefore not yet at great risk for non-disjunction trisomies based on maternal age. METHODS: The patients were counseled regarding the following: 1) the age-related risk of chromosomal abnormalities, 2) the procedure-related risk of fetal loss, 3) clinical implications of chromosomal abnormalities, 4) the need for complete counseling by a certified genetic counselor, and 5) the patient expense of $600-1200 if third-party reimbursement was not available. Patients were recruited from the private practice of the senior author at the New York Hospital--Cornell Medical Center. Five hundred ninety-one patients were offered prenatal genetic diagnosis. The outcome measure was the patient's decision to undergo prenatal diagnosis even though the risk of a non-disjunction trisomy was expected to be low based on maternal age. Amniocentesis was performed in 128 patients and chorionic villus sampling in five. RESULTS: One hundred thirty-three patients (22.5%) chose prenatal diagnosis. Karyotype was obtained in 131 procedures, but two were unsuccessful. One of the 131 karyotypes was abnormal and the patient chose to terminate the pregnancy. CONCLUSIONS: The data showed the following: 1) Inappropriate influence of patients by the health provider was not evident; 2) routine offering of genetic diagnosis enhanced the autonomy of pregnant women; 3) the potential increase in the loss of pregnancies that accompanies this practice is ethically justified; and 4) there are no compelling cost-benefit objections to such a practice.

Clonal analysis of solitary follicular nodules in the thyroid.

Accumulated data using functional, morphologic, and histochemical analysis suggests that follicular proliferations in the thyroid include polyclonal and monoclonal patterns with encapsulated follicular adenomas most frequently monoclonal, and other nodules generally polyclonal. However, examples of polyclonal carcinomas or adenomas raise the possibility that histologically similar lesions may arise through different pathogenetic mechanisms. The authors have performed a clonal analysis of histologically benign and malignant thyroid nodules in seven women using HPRT (hypoxanthine phosphoribosyl transferase) and PGK (phosphoglycerate kinase) restriction fragment length polymorphisms (RFLPs) on the X chromosome. These RFLPs used in concert with methylation-sensitive restriction endonucleases HpaII and HhaI permit distinction of active and inactive X chromosomes. DNA from a multinodular goiter showed equal sensitivity of both X chromosome RFLP alleles to a methylation-sensitive restriction endonuclease, consistent with a polyclonal origin. In contrast, three solitary follicular nodules and three carcinomas displayed predominant sensitivity of a single RFLP allele, consistent with a monoclonal origin. Although further detailed studies will be necessary to understand polyclonal origins reported for some adenomas, our data from a limited number of samples supports a predominantly monoclonal origin, and possible neoplastic pathogenesis, for many solitary adenomatous nodules in the thyroid.

Heterogeneity of clinical severity and molecular lesions in Aicardi syndrome.

All patients with Aicardi syndrome are female or have a 47,XXY karyotype. This finding, along with a report of an Aicardi syndrome patient with an Xp22/autosome translocation, led to the hypothesis that Aicardi syndrome might be caused by an X-linked dominant, male-lethal mutation on the short arm of the X chromosome. To study this hypothesis, we investigated X chromosome inactivation patterns in peripheral lymphocytes from seven patients. We used two methods: methylation-sensitive restriction enzyme analysis and segregation of the active X chromosome in somatic cell hybrids. We found that three of seven cytogenetically normal girls with Aicardi syndrome had profoundly skewed X-inactivation in their lymphocytes, supporting the concept that Aicardi syndrome is X linked. Three of the five girls with the greatest degree of psychomotor retardation and the poorest seizure control had skewed X-inactivation. In contrast, the two highest-functioning children had random X-inactivation. We screened DNA using eight polymorphic probes from the Xp22 region but were unable to identify a deletion in any of the seven patients. Nonrandom X-inactivation in lymphocytes and possibly other tissues in some, but not all, patients with Aicardi syndrome may reflect heterogeneity of their molecular lesions.

X chromosome inactivation patterns in obligate carriers of X-linked lymphoproliferative syndrome.

To determine whether the gene defect that causes X-linked lymphoproliferative syndrome (XLP) results in a selective disadvantage in proliferation or survival of leukocytes, we analyzed X chromosome inactivation patterns in neutrophils, T cells, and B cells from two unrelated obligate carriers of XLP. Analysis of DNA methylation patterns and production of somatic cell hybrids demonstrated that all three cell lines from both women exhibited normal, random X chromosome inactivation. These findings indicate that the XLP gene defect does not result in a global defect in proliferation or survival of T cells or B cells. It remains possible that a subset of T or B cells or natural killer cells may be selectively affected. It is also possible that the gene defect alters function but not proliferation or survival of T or B cells.

Trisomy 18 score: a rapid, reliable diagnostic test for trisomy 18.

We developed a bedside scoring system for diagnosis of trisomy 18 in the immediate neonatal period. Points are assigned for the presence of features known to occur in trisomy 18: five points for the presence of features previously reported in 50% or more of affected infants; three points for features reported to occur in between 10% and 50% of affected individuals; and one point for features known to occur in less than 10% of infants with the disorder. Using the scoring system, we evaluated two cohorts of patients: those in whom a diagnosis of trisomy 18 was previously established (retrospective group) and those in whom the diagnosis was suspected but not yet proved (prospective group). The average score in the retrospective series (n = 25) was 96.7, and no patient scored less than 70. Twenty-two patients were evaluated prospectively; in all cases the presence or absence of trisomy 18 was correctly predicted. The average score in the 11 patients without trisomy 18 was 41.4, and all patients scored 60 or less. In the 11 patients confirmed to have trisomy 18, the average score was 94.3, with a range of 70 to 113. This scoring system is an accurate, reproducible method for predicting trisomy 18 in neonates with multiple congenital malformations.

Aglossia with congenital absence of the mandibular rami and other craniofacial abnormalities.

We describe a severe first branchial arch abnormality including nearly complete absence of mandible, hypoplasia of the maxilla and the zygomatic arches, and complete gingival fusion in a chromosomally normal child born to a nonconsanguineous couple who deny prenatal exposures. A tight orbicularis oris muscle caused the lips to be constantly pursed. Intraoral contents could only be defined after the fused gingiva were separated. The infant had hypoplasia of the buccal cavity with a persistent membrane separating it from the pharynx; palate structures and tongue were absent. The orbits and midface were severely hypoplastic. However, the ears were normal in shape and only slightly low in position. There was unilateral optic nerve coloboma and coronal craniosynostosis. The only noncraniofacial malformation was an atrial septal defect. Embryologically, there is severe malformation of structures arising from the cephalic neural crest cells of both the maxillary and mandibular prominences of the first branchial arch. However, the first branchial cleft region was spared.