Richard M. Pauli

Maternal and fetal sequelae of anticoagulation during pregnancy

Review of published cases of pregnancies in which coumarin derivatives or heparin were administered demonstrates that use of either class of anticoagulant carries substantial risks. Of 418 reported pregnancies in which coumarin derivatives were used, one-sixth resulted in abnormal liveborn infants, one-sixth in abortion or stillbirth and, at most, two-thirds in apparently normal infants. In addition to the expected hemorrhagic complications, fetal effects of coumarin derivative administration include a specific embryopathy and central nervous system abnormalities. All available cases (including unpublished ones) of warfarin embryopathy and central nervous system abnormalities following gestational exposure to coumarin derivatives are reviewed, various complications are tabulated, critical periods of teratogenesis are discussed and possible mechanisms proposed. The use of heparin during gestation does not result in a significantly better outcome of pregnancy. In 135 published cases, the infants in one-eighth were stillborn, in one-fifth premature (a third of whom died) and, again at most, in two-thirds apparently normal. Because of the substantial risks of both clases of anticoagulants, and the inherent risks of pregnancy complicated by the indications for anticoagulation, prevention of pregnancy is usually indicated. If pregnancy occurs, a relatively normal outcome can be anticipated in about two-thirds of the pregnancies regardless of the anticoagulant used. Heparin does not appear to be a clearly superior alternative to coumarin derivatives.

Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the glycine and serine residue (GS) activation domain of activin A type I receptor/activin‐like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP‐like heterotopic ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP‐plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP‐plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP‐plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype‐phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development. Hum Mutat 0, 1–12, 2008.

Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia

Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis. Its population incidence has been estimated at 1 per million in the United Kingdom, but it is likely to be higher in the Middle East and Gulf States. Affected individuals are asymptomatic in early childhood. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.

Apnea and sudden unexpected death in infants with achondroplasia

Thirteen infants with achondroplasia and sudden unexpected death or unexplained apnea were discovered through nonsystematic retrospective case collection. Most were initially thought to have died from sudden infant death syndrome. However, historical and pathologic findings suggest that many of these infants had apnea and sudden unexpected death secondary to acute or chronic compression of the lower brainstem or cervical spinal cord. Infants with achondroplasia evidently are at considerably increased risk for such deaths between 1 month and 1 year of age. Appropriate intervention, given these previously unrecognized risks, may include cervical restraint, polysomnographic evaluation, and apnea monitoring.

Ventricular noncompaction and distal chromosome 5q deletion.

We describe a 7 1/2-year-old girl with mildly unusual phenotype and complex heart disease including ventricular myocardial noncompaction. She was found to have a distal 5q deletion, del(5)(q35.1q35.3). Fluorescent in situ hybridization showed that this deletion included the locus for the cardiac specific homeobox gene, CSX. This suggests that some instances of ventricular myocardial noncompaction may be caused by haploinsufficiency of CSX.

Majewski osteodysplastic primordial dwarfism type II (MOPD II): Natural history and clinical findings

A description of the clinical features of Majewski osteodysplastic primordial dwarfism type II (MOPD II) is presented based on 58 affected individuals (27 from the literature and 31 previously unreported cases). The remarkable features of MOPD II are: severe intrauterine growth retardation (IUGR), severe postnatal growth retardation; relatively proportionate head size at birth which progresses to true and disproportionate microcephaly; progressive disproportion of the short stature secondary to shortening of the distal and middle segments of the limbs; a progressive bony dysplasia with metaphyseal changes in the limbs; epiphyseal delay; progressive loose‐jointedness with occasional dislocation or subluxation of the knees, radial heads, and hips; unusual facial features including a prominent nose, eyes which appear prominent in infancy and early childhood, ears which are proportionate, mildly dysplastic and usually missing the lobule; a high squeaky voice; abnormally, small, and often dysplastic or missing dentition; a pleasant, outgoing, sociable personality; and autosomal recessive inheritance. Far‐sightedness, scoliosis, unusual pigmentation, and truncal obesity often develop with time. Some individuals seem to have increased susceptibility to infections. A number of affected individuals have developed dilation of the CNS arteries variously described as aneurysms and Moya Moya disease. These vascular changes can be life threatening, even in early years because of rupture, CNS hemorrhage, and strokes. There is variability between affected individuals even within the same family.

Natural history of rhizomelic chondrodysplasia punctata

Rhizomelic chondrodysplasia punctata (RCP) is a rare autosomal recessive disorder with many associated medical complications. Prior to this study, natural history information about RCP was limited and based on experiences with small populations of affected individuals. We delineate the natural history of RCP through systematic analysis of 35 previously unreported individuals (as well as review of 62 literature cases with respect to survival and cause of death). Survival, growth, and developmental expectations and medical needs are summarized based upon experience with this population. Survival is greater among this population than previously reported, with 90% surviving up to 1 year and 50% surviving up to 6 years. Cause of death is most often respiratory problem. All infants with RCP have joint contractures, bilateral cataracts, and severe growth and psychomotor delays. Recommendations for health supervision of children with RCP and for parental counseling are presented.

Hajdu‐Cheney syndrome: Evolution of phenotype and clinical problems

Hajdu-Cheney syndrome is a rare, autosomal dominant disorder comprising acroosteolysis of the distal phalanges with associated digital abnormalities, distinctive craniofacial and skull changes, dental anomalies, and proportionate short stature. The clinical and radiologic characteristics of Hajdu-Cheney syndrome develop and progress with age. Many of the medical problems that arise in this syndrome cluster in specific age ranges. Case reports of six affected individuals in two additional families and a summary of the English literature is presented with emphasis on the changing physical findings and medical sequelae over time.

Long-term survival in typical thanatophoric dysplasia type 1

Thanatophoric dysplasia (TD), a severe skeletal dysplasia, is virtually always lethal neonatally, although a few previous reports have documented survival up to 4.75 years. We present a patient with survival beyond age 9 years and summarize his growth, development and medical history. The common Arg248Cys mutation in the extracellular region of fibroblast growth factor receptor 3 (FGFR3) was identified, eliminating the possibility that his long-term survival is attributable to an atypical mutation. This patient (and at least one other TD long-term survivor) have a rare skin disorder, acanthosis nigricans, which also occurs in Crouzon syndrome when caused by a FGFR3 mutation. Therefore, any molecular model of the origin of acanthosis nigricans secondary to FGFR3 mutations must account for the association of diverse mutations and these cutaneous effects.

Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: Bent but not broken

We describe a fifth instance of hypophosphatasia presenting with prenatal findings suggestive of a very severe bone dysplasia but with a subsequently benign course. Spontaneous improvement of long-bone angulation began prenatally. The postnatal course has been encouraging. This sixth clinical form of hypophosphatasia, which we suggest should be called the benign prenatal form of hypophosphatasia, should be added to the differential diagnostic possibilities considered when angulation or bowing of long bones is discovered prenatally.