Clinical characteristics.

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities.

Diagnosis/testing.

The diagnosis of MOPDII is established in a proband with suggestive findings and biallelic loss-of-function pathogenic variants in PCNT identified by molecular genetic testing.

Management.

Treatment of manifestations: Relies on symptomatic care from multidisciplinary specialists in pediatrics, orthopedics, dentistry, neurosurgery, cardiology, nephrology, endocrinology, and medical genetics, and from educators when learning difficulties are an issue.

Surveillance: Routine follow up of growth and development as well as monitoring of any known or potential complications regarding hip or spine deformity, dental abnormalities, cerebrovascular disease, coronary artery disease, hypertension and/or renal disease, diabetes mellitus, and/or educational issues.

Agents/circumstances to avoid: Growth hormone supplementation in the absence of growth hormone deficiency; excessive nutritional supplementation in infancy.

Genetic counseling.

MOPDII is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PCNT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the PCNT pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

MOPDII should be suspected in individuals with the following clinical and radiographic findings and family history.

Clinical findings

• Severe pre- and postnatal growth restriction
• Extreme microcephaly
• Skeletal dysplasia
• Distinctive facial features (see Figure 1) including:
  • Prominent nose with wide nasal bridge and broad root
  • Low-hanging columella
  • Ears with simple structure and attached lobes
• Abnormal dentition
  • Microdontia
  • Premature tooth loss
• Global vascular disease
  • Moyamoya vasculopathy
  • Aneurysms (predominantly central nervous system)
  • Coronary artery disease with premature myocardial infarctions
  • Renal artery disease
• Chronic kidney disease
• Insulin resistance / diabetes mellitus
• Hypertension
• Hematologic abnormalities
  • Thrombocytosis
  • Anemia
• High-pitched nasal voice

Figure 1

A-C. Same young man with MOPDII at ages 1 year, 5 years 7 months, and 16 years 6 months D. Secondary teeth are small and dysplastic with enamel hypoplasia.

Imaging findings

• Skeletal
  • Mesomelia
  • Slender long bones
  • Progressive widening of metaphyses
  • Epiphyseal ossification delay
  • Dislocation or subluxation of radial heads
  • Brachymesophalangy (See Figure 1.)
  • Small iliac wings with flat acetabular angles
  • Coxa vara
  • Slipped capital femoral epiphysis (See Figure 2.)
  • Scoliosis (See Figure 2.)
• Neuroimaging
  • Moyamoya
  • Intracranial aneurysms

Figure 2

A. Right slipped capital femoral epiphysis in a female age 26 months, subsequently treated with in situ pinning B. 110-degree thoracolumbar scoliosis in a male age 13 years, subsequently treated with posterior spinal fusion with instrumentation

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of MOPDII is established in a proband with suggestive findings and biallelic loss-of-function pathogenic (or likely pathogenic) variants in PCNT identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of only one known PCNT pathogenic variant does not rule out a diagnosis of the disorder, as occasionally an in trans cryptic variant not detected by conventional molecular analysis has been implicated by functional studies establishing absence of PCNT protein [Bober et al 2012].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings may be more likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MOPDII has not been considered may be more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common of the microcephalic primordial dwarfism syndromes, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and which may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities [Bober & Jackson 2017, Duker et al 2021].

Anticipated life expectancy is shortened due to the associated comorbidities, which when untreated can lead to early death, predominately in early adulthood (age range 7-41 years) [Duker et al 2021].

More than 150 individuals with a molecularly confirmed diagnosis have been identified [Bober & Jackson 2017].

The following description of the phenotypic features associated with this condition is based on the most recent review of 47 individuals with molecularly confirmed MOPDII [Duker et al 2021].

Growth restriction and microcephaly. All individuals have extreme growth restriction. This has been identified as early as the first trimester of pregnancy and continues lifelong. At birth, average length was 7.0 standard deviations (SD) below the mean, weight 3.9 SD below the mean, and head circumference 8.5 SD below the mean. At skeletal maturity, average height was 10.3 SD below the mean, weight 14.3 SD below the mean, and head circumference 8.5 SD below the mean. Average adult height is approximately 100 cm.

Body habitus evolves with time. Infants and young children have decreased subcutaneous fat; truncal obesity tends to develop through puberty. In contrast to weight gain in age-related peers, the average expected daily weight gain in individuals with MOPDII is 2 g/day throughout the life span, from infancy to skeletal maturity. Appropriate weight gain expectations are paramount to avoid excessive and unnecessary nutritional interventions [Bober et al 2012, Bober & Jackson 2017, Duker et al 2017] (see Management).

Skeletal dysplasia. Mesomelia is present at birth and appears to become more prominent over time. Slender long bones are noted at birth with an epiphyseal ossification delay and progressive widening of the metaphyses. Radial head can dislocate or sublux in childhood, leading to limited range of motion at the elbow.

Ivory and cone-shaped phalangeal epiphyses have been described; fifth finger clinodactyly and brachymesophalangy are common.

Iliac wings are small with flat acetabular angles.

Scoliosis may occur and can rapidly progress in late childhood / puberty, leading to the need for spinal fusion [Hall et al 2004, Bober & Jackson 2017].

Associated hip pathology includes coxa vara, coxa valga, developmental dysplasia, dislocation/subluxation, proximal femoral epiphysiolysis, and avascular necrosis. Eight of 12 individuals had hip pathology, some unilaterally (equaling 50% of the total hips). Developmental coxa vara was the most common finding, often beginning with a slipped capital femoral epiphysis and progressing to severe coxa vara, typically identified between ages two and five years [Karatas et al 2014] (see Table 5 and Figure 2).

Dental abnormalities. Primary teeth are small for age but may appear proportionate to the mouth. Primary teeth can have deficient enamel and can be abnormally shaped. Hypodontia can occur.

Secondary teeth tend to be more affected. They are disproportionately small, dysplastic, and can have enamel hypoplasia. They are typically poorly rooted, and chewing can be affected. In many individuals, secondary teeth either prematurely shed or are extracted, and are replaced with dentures and/or implants [Hall et al 2004, Kantaputra et al 2011, Bober & Jackson 2017] (see Figure 1).

Hematologic abnormalities. Asymptomatic thrombocytosis, leukocytosis, and anemia are common [Unal et al 2014, Bober & Jackson 2017, Duker et al 2021].

Cerebrovascular. From birth onward, 25 of 47 individuals were diagnosed with intracranial aneurysms (with 30 having more than one aneurysm), 22 were diagnosed with moyamoya vasculopathy, 17 had both moyamoya vasculopathy and intracranial aneurysms, and 17 had neither. Approximately half of those diagnosed with moyamoya vasculopathy and/or aneurysms ultimately had a stroke (ischemic or hemorrhagic, respectively). Aneurysm risk appeared to be relatively steady through childhood, whereas moyamoya vasculopathy risk was higher prior to age five years [Duker et al 2021].

Cardiovascular. Elevated blood pressure was observed in almost 50% of teens and young adults. The many intertwined comorbidities that contribute to hypertension include moyamoya vasculopathy, renal disease, coronary artery disease, dyslipidemia, and insulin resistance.

In a cohort of 47 individuals, eight had myocardial infarctions as young adults (range 17-33 years; mean age 24±5.2 years; median age 24 years); multiple individuals had more than one acute coronary event.

Approximately 25% of individuals had cardiac malformations, including atrial septal defect, ventricular septal defect, and persistent patent foramen ovale. One individual had multiple cardiac rhabdomyomas [Duker et al 2021].

Other vasculopathies. MOPDII is associated with global vascular disease. Besides involvement of cerebral vasculature as well as renal and coronary vasculature, the external carotid artery has been stenotic as well as the site of an aneurysm. At least six individuals have had difficulties with femoral artery occlusion after catheterization procedures [Duker et al 2021].

Renal. Among 47 individuals, one third had chronic kidney disease (cause not specified). Mean age of the diagnosis of Stage III chronic kidney disease was 22 years. Additionally, two individuals had a kidney transplant, at ages 21 years and 23 years, one of the two had a renal artery aneurysm.

Another individual who had renal artery stenosis in addition to a renal artery aneurysm ultimately had a partial infarct of a kidney.

Six individuals had nephrolithiasis in early adulthood; all were on anti-hypertensive medications at the time of the diagnosis of nephrolithiasis.

Congenital anomalies included accessory/duplicated renal arteries in seven males and no females [Duker et al 2021].

Genitourinary. Two of 25 males had hypospadias and 11 had cryptorchidism or retractile testes [Duker et al 2021].

Insulin resistance and/or diabetes mellitus. Eighteen of 21 individuals older than age four years had insulin resistance or diabetes [Huang-Doran et al 2011].

Seventeen of 46 individuals (in a different but overlapping cohort) had insulin resistance and/or diabetes, typically detected in adolescence [Duker et al 2021].

These issues can also lead to dyslipidemia and fatty liver [Huang-Doran et al 2011].

Cognitive ability. Despite the significant microcephaly, intellectual development is generally in the typical to borderline range, and social skills are excellent. Many individuals have been described as hyperactive with easy distractibility in childhood [Hall et al 2004; Authors, personal observation]. However, those who have had strokes due to vascular disease have had more impairment [Bober & Jackson 2017]. Attending typical schools is expected, and some have attended college. However, it can be challenging for adults to live independently [Hall et al 2004].

Additional features

• Skin:
  • Acanthosis nigricans, repeatedly documented, is likely related to concomitant insulin resistance [Hall et al 2004, Bober & Jackson 2017].
  • Café au lait patches have been described, with areas of hypopigmentation later in life.
  • "Wizened hands" with multiple creases developing in childhood have been noted (see Figure 1).
• Neuroimaging findings can include simplified gyral patterns and hypoplasia of the corpus callosum [Hall et al 2004, Abdel-Salam et al 2020].
• Subglottic stenosis, described in some individuals, required tracheostomy in at least two affected individuals [Hall et al 2004; Authors, unpublished data].
• Craniosynostosis has been infrequently described, at times requiring surgical intervention. One child had bilateral coronal synostosis recognized in the neonatal period which required repair [Hall et al 2004; Abdel-Salam et al 2020; Authors, unpublished data].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], MOPDII is referred to as PCNT-related microcephalic osteodysplastic primordial dwarfism and is included in the primoridal dwarfism and slender bones group.

Prevalence

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is rare. More than 150 individuals with molecularly confirmed MOPDII have been identified across many populations worldwide [Bober & Jackson 2017].

Many different loss-of-function variants have been identified. Founder variants reported in specific populations include the following:

• Colombia. c.1468C>T (p.Gln490Ter) [Pachajoa et al 2014; Authors, unpublished data]
• Israeli Druze population. c.3465-1G>A (p.Ala1157ProfsTer36) [Weiss et al 2020]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MOPDII, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Growth hormone supplementation in the absence of growth hormone deficiency has not been helpful, and in fact can contribute to morbidity [Hall et al 2004, Huang-Doran et al 2011, Bober et al 2012].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected child are usually heterozygotes (i.e., presumed to be carriers of one PCNT pathogenic variant based on family history).
• Molecular genetic testing for the parents of a proband can be performed to confirm that both parents are heterozygous for a PCNT pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• If both parents are known to be heterozygous for a PCNT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with MOPDII are obligate heterozygotes (carriers) for a pathogenic variant in PCNT.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a PCNT pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the PCNT pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the PCNT pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Biallelic loss-of-function PCNT pathogenic variants result in loss of cellular pericentrin protein [Griffith et al 2008, Rauch et al 2008]. Pericentrin is a large 360-kd coiled protein with a C-terminal PACT domain that targets it to the centrosome. It is a major component of the pericentriolar material that acts as a microtubular nucleation center to organize the mitotic spindle. Loss of pericentrin therefore perturbs mitosis in the cells of individuals with MOPDII [Rauch et al 2008], likely reducing cell number during development, resulting in extreme growth failure and microcephaly [Klingseisen & Jackson 2011]. Pericentrin also acts as a scaffold for signaling proteins, and may also reduce growth through acting in downstream ataxia-telangiectasia and Rad3-related (ATR) pathway signaling [Griffith et al 2008, Tibelius et al 2009].

Mechanism of disease causation. Loss of function

PCNT-specific laboratory technical considerations. While single amino acid substitutions could cause loss of function, none has been reported to date in individuals with MOPDII.

Acknowledgments

The authors wish to wholeheartedly thank the Potentials Foundation and the Walking with Giants Foundation for their support of families worldwide with MOPDII, as well as for their support of research into this condition. Work in the Jackson lab has been supported by the European Union's Horizon 2020 research and innovation program ERC Advanced Grant (grant agreement 788093), and by a UK Medical Research Council (MRC) Human Genetics Unit core grant (MRC, U127580972).

Revision History

• 30 March 2023 (sw) Revision: Nosology of Genetic Skeletal Disorders: 2023 Revision [Unger et al 2023] added to Nomenclature
• 30 December 2021 (bp) Review posted live
• 12 October 2021 (mb) Original submission

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