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At a glance

A brachymelic primordial disproportionate dwarfism associated with facial dysmorphism and neurologic impairment.

Synonyms

Microcephalic Osteodysplastic Primordial Dwarfism (MOPD), Type 1, 2, and 3; MOPD 1, 2, and 3; Brachymelic Primordial Dwarfism; Taybi-Linder Syndrome (MOPD 1); Low-Birth-Weight Dwarfism with Skeletal Dysplasia.

History

First described in 1967 by Hooshang Taybi, an Iranian-American pediatric radiologist and David Linder, an American pathologist. They described two siblings with dwarfism, skeletal abnormalities, and severe brain malformations.

Incidence

Slightly more than 100 cases have been described (∼42 with MOPD 1, ∼60 with MOPD 2, and <5 with MOPD 3).

Genetic inheritance

Autosomal recessive. Parental consanguinity has been reported for some cases. MOPD 1 is caused by mutations in the RNU4ATAC gene (U4AT-AC small nuclear RNA, a crucial component of the minor spliceosome) on chromosome 2q14.2, MOPD 2 by mutations in the PCNT (Pericentrin) gene on chromosome 21q22.3, and in MOPD 3 the underlying genetic defect is unknown, but is assumed to be the same as for MOPD 1. MOPD Types 1 and 3 basically present with the same clinical spectrum and only subtle variations with regards to craniofacial and cerebral anomalies and radiographic findings (see “skeletal anomalies”), thus the two types are generally considered to be variants of the same disease (MOPD 1/3).

Diagnosis

Based on the clinical and radiographic findings. Genetic molecular testing can be used to confirm the final diagnosis.

Clinical aspects

Some of the clinical features like severe pre- and postnatal growth retardation, marked microcephaly and skeletal dysplasia are common to all three types of MOPD, whereas severe brain anomalies with profound developmental delay, ectodermal anomalies, and shortened life expectancy (often <12 months) are typical for MOPD 1/3. Approximately half of all MOPD 1/3 patients die from infectious causes (see below). The reported average life expectancy for MOPD 1/3 varies widely depending on the underlying mutation and is between 10 and 78 months. Cerebral vasculopathy is found in almost 20% of MOPD 2 patients (but has not been reported in MOPD 1/3) and manifests as multiple cerebral aneurysms, tortuous vessels, or ☞Moya-Moya disease, can exacerbate during puberty and may cause life-threatening cerebral hemorrhages and strokes already early in life. Oligohydramnios with severe intrauterine and postnatal growth retardation are almost always present. Facial dysmorphism and neck anomalies include profound microcephaly with already closed anterior fontanelle at birth with possible craniosynostosis, prominent occiput, sloping forehead, low-set and small, dysplastic, posteriorly rotated ears, large protruding eyes, strabismus, big, prominent nose with downturned tip, unilateral choanal atresia, mandibular hypoplasia, micro-/retrognathia, high-arched and narrow palate, multiple, thick labial frenula, widely-spaced teeth, microdontia, hypoplastic or absent roots, enamel hypocalcification, and cavities with early loss of teeth, and short neck. Central nervous system involvement (typically in MOPD 1 and 3) can manifest with delayed psychomotor development, seizures, micrencephaly, hypoplastic frontal lobes, gyral anomalies (eg, lissencephaly, pachygyria), neuronal heterotopia, corpus callosum agenesis, enlarged lateral ventricles, and hypoplastic cerebellum and agenesis of the cerebellar vermis. Visual and sensorineural (and/or conductive) hearing impairment have been reported in some patients. Lissencephaly in MOPD 1 and 3 may show different microarchitecture and -layering. Despite all these findings, the patients are often described as having a very friendly and cheerful personality. MOPD 2 patients have often only mild developmental delay, some even have finished high school or college and can frequently cope surprisingly well in daily life. However, due to their extremely short stature, they are unable to live independently. Skeletal features can include hip dislocation, joint flexion deformities, flexion contractures in the big joints, short limbs, brachydactyly, clinodactyly of the fifth digit, delayed bone age, scoliosis with abnormal vertebral size and shape (cervical clefts, platyspondyly), rib anomalies, coxa vara, flared iliac wings, shallow acetabula, delayed metaphyseal maturation, and bowed femura and humeri. MOPD 1 is characterized by short and bowed long bones, whereas typical findings in MOPD 3 may include dolichocephaly, elongated clavicles, cleft cervical vertebral arches, lumbar platyspondyly, enlarged metaphyses, and marked pelvic dysplasia. Additional characteristic skeletal abnormalities in MOPD 2 may consist of relatively proportionate head size at birth that then progresses to true and disproportionate microcephaly with elongated midface. Most infants with MOPD 2 do not reach normal newborn size until the age of 2 and 5 years (!) have severely delayed ossification, small iliac wings with flat acetabular angles, coxa vara, proximal femoral epiphyseolysis, V-shaped distal femoral metaphyses, and triangular distal femoral epiphyses, as well as pseudoepiphyses of metacarpals, and short first metacarpals. Precocious puberty is frequently reported, particularly in affected girls, with thelarche at around 7 years and menarche at around 9 years of age. A few MOPD 2 patients have been reported with subglottic stenosis that lead to breathing problems in infancy and some patients required tracheostomy. Another patient was described with laryngomalacia and a vocal cord web. Renal dys- or hypoplasia was present in a few MOPD 2 patients. Urogenital anomalies may consist of micropenis, hypospadias, cryptorchidism, obstructive hydronephrosis. Endocrine dysfunction has occasionally been reported (eg, hypothyroidism, diabetes insipidus, hypogonadism). Anemia occurred in several patients and an increased susceptibility to infections or an abnormal immune response has been suggested. Ectodermal features in MOPD 1 and 3 include sparse hair or alopecia, dry and aged-appearing skin, pigmentation anomalies (multiple café-au-lait spots and freckling that develop in the first 2 years of life; dark pigmentation around the neck, on the trunk and in the axilla is often present at around 5 years of age; areas of hyper- and depigmentation occur later around puberty), bilateral simian creases, and decreased sweating. In infants, skin mottling is frequently present on the limbs and occasionally also involves the trunk. Tetralogy of Fallot and renal leakage have been described in one case. Another patient with MOPD 1 was described with ventricular septal defect, patent foramen ovale, pulmonary hypertension, and additionally suffered from narrowing of the spinal canal at C1-2 with C-2 posterior arch hypoplasia. MOPD 1 and 3 is frequently lethal within the first year of life, but survival into adolescence or early adulthood has sporadically been described. The reported causes of death are most often infections, such as meningitis, meconium peritonitis, aphthous stomatitis, airway infections with pneumonia, and sepsis. In quite a few case reports patients are pictured with tracheostomies, but no reference is made to the reasons or procedure-related complications. Some features are similar to ☞Seckel Syndrome; however, dwarfism in MOPD 1 and 3 is disproportionate due to the short limbs.

Precautions before anesthesia

Preoperative assessment should mainly focus on signs of difficult airway management and cervical spine anomalies. Blood work should at least include a complete blood count, serum electrolytes, creatinine, and urea. Thyroid function tests may be indicated if there are any signs of hypothyroidism or patients are known to be hypothyroid. Due to cerebral vasculopathy, patients suffering from MOPD 2 should be monitored with CT- or MRI-scanning to exclude pathologic vascular lesions since complications have been described (eg, rupture/hemorrhage, stroke, death) Anticonvulsant therapy should be continued until the morning of surgery and resumed as soon as possible postoperatively and given intravenously if oral intake is not possible. Developmental delay, particularly when combined with visual and hearing impairment may cause agitation and stress in the perioperative period, thus anxiolytic and sedative premedication and/or presence of a parent (or primary caregiver) for induction of anesthesia may be beneficial. Depending on the procedure, postoperative mechanical ventilation may be required and arrangements should be made beforehand.

Anesthetic considerations

Anesthesia in this condition has ...

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