Growth in individuals with Majewski osteodysplastic primordial dwarfism type II caused by pericentrin mutations

Abstract

Microcephalic primordial dwarfism (MPD) is a class of disorders characterized by intrauterine growth restriction (IUGR), impaired postnatal growth and microcephaly. Majewski osteodysplastic primordial dwarfism type II (MOPD II) is one of the more common conditions within this group. MOPD II is caused by truncating mutations in pericentrin (PCNT) and is inherited in an autosomal recessive manner. Detailed growth curves for length, weight, and OFC are presented here and derived from retrospective data from 26 individuals with MOPD II confirmed by molecular or functional studies. Severe pre-and postnatal growth failure is evident in MOPD II patients. The length, weight, and OFC at term (when corrected for gestational age) were À7.0, À3.9, and À4.6 standard deviation (SD) below the population mean and equivalent to the 50th centile of a 28-29-, 31-32-, and 30-31-week neonate, respectively. While at skeletal maturity, the height, weight, and OFC were À10.3, À14.3, and À8.5 SD below the population mean and equivalent to the size of 3-year 10-to 11-month-old, a 5-year 2-to 3-month-old, and 5-to 6-month-old, respectively. During childhood, MOPD II patients grow with slowed, but fairly constant growth velocities and show no evidence of any pubertal growth spurt. Treatment with human growth hormone (n ¼ 11) did not lead to any significant improvement in final stature. The growth charts presented here will be of assistance with diagnosis and management of MOPD II, and should have particular utility in nutritional management of MOPD II during infancy.

Genetics of Short Stature

“…Pericentrin ( PCNT) encodes a centrosomal protein in the microtubule network and the mutations cause MOPD II but also Seckel syndrome [66]. Moreover, clinical overlaps may occur between Seckel syndrome [56, 66], MOPD II [56, 66–68], Fanconi anemia ( FANC ) [56], LIG4 syndrome ( LIG4 ) [56, 69], and Nijimegen breakage syndrome ( NBS1 ) [56, 70–71]. Mutations in BLM cause Bloom syndrome which manifests as sun-sensitive skin and increased risk of malignancies, including leukemia, lymphoma, adeno-, and squamous cell carcinoma [72–73].…”

“…This group of syndromes can be caused by mutations in genes important for genome or nuclear stability (3M syndrome [78–80], Cornelia de Lange syndrome [81], Hutchinson-Gilford Progeria [82–83], microcephalic osteodysplastic primordial dwarfism type 2, MOPD II [67–68], SOFT syndrome [84–85]), chromatin remodeling (Floating-Harbor syndrome [86–88], Coffin-Siris syndrome [89]), RNA processing (microcephalic osteodysplastic primordial dwarfism type 1, MOPD I [90–91]), ubiquitination (Mulibrey nanism [92–94]), cytoskeletal interaction (primordial dwarfism due to CRIPT mutation [95]), microtubule organization (Alström syndrome [96]) or cholesterol biosynthesis (Smith-Lemli-Opitz syndrome [97], (Table 1). The patients are often born small for gestational age indicating that growth is affected during intrauterine life.…”

Investigating microcephaly

“…So history is vital to determine if there are prenatal environmental/maternal causes for a case of primary microcephaly, and if suspected the appropriate TOxoplasma/Rubella/Cytomegalovirus/Herpes (TORCH)±HIV screen, or MRI scan can be performed. Scrutiny of maternal notes should confirm the diagnosis: for example, phenylketonuria (rare now, but still possible if an affected mother strays from her strict diet during pregnancy), malnutrition or hypothyroidism; teratogens such as alcohol (noting that foetal alcohol syndrome is a difficult diagnosis to make7), recreational and medicinal drugs; or placental insufficiency. Brain disruptions can be caused by a twin pregnancy, maternal abdominal injury, placental abruption, maternal antibodies, but in some cases the aetiology remains undiscoverable.…”

A new mutation of the PCNT gene in a Colombian patient with microcephalic osteodysplastic primordial dwarfism type II: a case report

“…[1], the patient is well below -2 standard deviations; this leaves the possibility that this difference occurs as a consequence of the origin and population group of the patient east of Antioquia (Colombia), unlike the sample of patients used by Bober et al ., which belong to the registry of patients with MOPD II at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, DE, USA (see Table 1) [1]. …”

“…Microcephalic osteodysplastic primordial dwarfism (MOPD) is a syndrome characterized by the presence of intrauterine growth restriction, post-natal growth deficiency, microcephaly and a similar phenotype to Seckel syndrome [1]. This condition was initially described by Majewski et al .…”