Pycnodysostosis
Summary
Clinical characteristics.
Pycnodysostosis is characterized by short-limbed short stature, typical facial appearance (convex nasal ridge and small jaw with obtuse mandibular angle), osteosclerosis with increased bone fragility, acroosteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. In affected individuals, the facial features become more prominent with age, likely due to progressive acroosteolysis of the facial bones, but can usually be appreciated from early childhood, particularly the small jaw and convex nasal ridge. Additional features include dental and nail anomalies. Intelligence is typically normal with mild psychomotor difficulties reported in some individuals.
Diagnosis/testing.
The diagnosis of pycnodysostosis can be established in a proband with characteristic clinical and radiographic features and/or biallelic pathogenic variants in CTSK identified by molecular genetic testing.
Management.
Treatment of manifestations: Growth hormone therapy; environmental or occupational modifications as needed; orthopedic management of fractures and scoliosis; craniofacial and neurosurgical management as required for cleft palate, craniosynostosis, maxillary and mandibular hypoplasia; pulmonology and sleep medicine specialist management of obstruction sleep apnea; consultation with expert anesthetist prior to any planned surgery; dental and orthodontic care for dental anomalies; standard management per ophthalmologist for vision concerns.
Surveillance: Annual physical examination including assessment for scoliosis, asymmetry, frequency of fractures, weight and nutrition, and psychological assessment; polysomnography every two years; annual evaluation with specialist dentist and ophthalmologist.
Agents/circumstances to avoid: If general anesthesia is needed, consider the possibility of difficult intubation prior to scheduling anesthesia.
Pregnancy management: In individuals with a small pelvis, delivery by cæsarean section should be considered. However, each individual should be assessed by an obstetrician and anesthetist familiar with skeletal dysplasia.
Genetic counseling.
Pycnodysostosis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CTSK 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 CTSK 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.
Diagnosis
Formal diagnostic criteria for pycnodysostosis have not been established, however the radiographic features of acroosteolysis, osteosclerosis, and loss of the normal angle of the jaw are almost pathognomonic.
Suggestive Findings
Pycnodysostosis should be suspected in individuals with the following clinical, radiographic, and laboratory findings.
Clinical findings
- Short-limbed short stature in all individuals (prenatal onset in ~30%)
- Brachydactyly
- Craniofacial findings
- Frontal bossing
- Persistently open anterior fontanelle
- Prominent nose with convex nasal ridge
- Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
- Stridor, laryngomalacia, and obstructive sleep apnea
- Prominent eyes with blueish sclera
- High arched palate / grooved palate
- Dental anomalies (e.g., delayed eruption of deciduous and permanent teeth, persistence of deciduous teeth resulting in a double row of teeth, hypodontia)
- Nail anomalies (e.g., dysplastic, grooved, flattened)
Radiographic findings (see Figure 1)
Figure 1.
- Generalized progressive osteosclerosis, particularly of the long bones
- Acroosteolysis of the terminal phalanges
- Non-pneumatized mastoids
- Delayed fusion of the cranial sutures
- Obtuse mandibular angle due to loss of the normal mandibular (gonial) angle
- Increased incidence of fractures
- Clavicular dysplasia, congenital pseudarthrosis of the clavicle
Laboratory findings
- Normal serum calcium, phosphate, vitamin D, and alkaline phosphatase
- Growth hormone deficiency
- Low IGF-1
- No abnormalities of other pituitary hormones
Family history 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 pycnodysostosis can be established in a proband with characteristic clinical and radiographic features and/or biallelic pathogenic variants in CTSK identified by molecular genetic testing (see Table 1).
Note: Identification of biallelic CTSK variants of uncertain significance (or identification of one known CTSK pathogenic variant and one CTSK variant of uncertain significance) does not establish or rule out the diagnosis of this disorder.
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 are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with osteosclerosis and/or short stature are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and radiographic findings suggest the diagnosis of pycnodysostosis, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of CTSK is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
- A multigene panel that includes CTSK and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by osteosclerosis and short stature, comprehensive genomic testing (which does not require the clinician to determine which gene is likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
---|---|---|
CTSK | Sequence analysis 3 | ~100% 4 |
Gene-targeted deletion/duplication analysis 5 | One reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Review of approximately 35 pathogenic variants in all available published case literature, ClinVar [Landrum et al 2014], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
A 301-bp Alu sequence insertion in intron 7 that creates a new potential splice acceptor site [Arman et al 2014]
Clinical Characteristics
Clinical Description
Pycnodysostosis is characterized by short stature, typical facial appearance (small jaw with obtuse mandibular angle and convex nasal ridge), osteosclerosis with increased bone fragility, acroosteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. In affected individuals, the facial features become more prominent with age, likely due to progressive acroosteolysis of the facial bones, but can usually be appreciated from early childhood, particularly the small jaw and convex nasal ridge [Turan 2014].
A comprehensive review of previously published reports [Xue et al 2011] identified 159 individuals including 59 unrelated families with confirmed homozygous or compound heterozygous pathogenic variants in CTSK. A further 27 affected individuals from 17 unrelated families were recently described, with molecular data available for 14 families [Bizaoui et al 2019]. The following description of the phenotypic features associated with pycnodysostosis is based on these reports.
Table 2.
Feature | % of Persons w/Feature | |
---|---|---|
Clinical | Short limb, short stature | ~100% |
Intrauterine growth restriction | ~30% | |
Brachydactyly | >90% | |
Frontal bossing | >80% | |
Persistently open anterior fontanelle | 80% | |
Convex nasal ridge | ~70% | |
Small jaw | >70% | |
Midface retrusion | 60% | |
Proptosis | 60% | |
Blueish sclerae | 30%-40% | |
Obstructive sleep apnea | >65% | |
Increased incidence of fractures | ~70% | |
Nail anomalies | >50% | |
Dental anomalies | 30%-40% | |
Radiographic | Osteosclerosis | ~100% |
Acroosteolysis of the terminal phalanges | >90% | |
Non-pneumatized mastoids | 80% | |
Delayed fusion of cranial sutures | 67% | |
Obtuse mandibular angle | 65% | |
Clavicular dysplasia | 25% |
Growth deficiency / short stature. Short stature is reported in almost 100% of individuals with pycnodysostosis. Individuals typically develop short stature by early childhood with decreased growth velocity, although 30% are reported to have intrauterine growth deficiency. Limbs are often disproportionately short compared to the trunk, with rhizo-, meso-, and acromelia. Documented adult heights are typically <150 cm for males (average 2.9 SD below the mean) and 130-134 cm for females (average 4.1 SD below the mean) [Bizaoui et al 2019].
About 50% have growth hormone deficiency but almost all have low IGF-1 levels. Administration of growth hormone has been shown to result in a satisfactory elevation in IGF-1 levels and near-normalization of adult height and skeletal proportions [Rothenbühler et al 2010].
Individuals with a growth hormone deficiency often also have pituitary hypoplasia identified on head imaging; no other abnormalities in pituitary hormones or pubertal development have been detected [Turan 2014].
Three individuals (2 diagnosed clinically and 1 with a molecular diagnosis) have been reported with taller-than-expected stature including an adult Mexican male of 153 cm (-1.9 SD), an adult Mexican female of 150 cm (-0.6 SD), and a Chinese boy age eleven years with normal height (137cm; -0.9 SD) [Zheng et al 2013, Valdes-Flores et al 2014].
Craniofacial appearance. The characteristic facial features (midface retrusion due to hypoplastic maxilla and small jaw with an obtuse mandibular angle) can become more apparent with age but are often detectable in infants, along with large anterior and posterior fontanelles and open cranial sutures with frontal and parietal bossing [Appelman-Dijkstra & Papapoulos 2016]. Additional common facial features include a convex nasal ridge. Less common features include proptosis with blueish sclera, and cleft palate or high palate with a midline groove [Bizaoui et al 2019]. The apparent palatal midline groove is due to narrow palate with shallow vault and fallen palatal wings with prominent median palatal raphe in eight individuals studied by Otaify et al [2018].
Skeletal. The second most common feature (after short stature) is increased bone density (osteosclerosis), which occurs throughout the skeleton and is progressive. The medullary canals, while often narrowed, remain present with evidence of hematopoiesis.
More than 90% of reported individuals have short hands and feet with short digits and progressive acroosteolysis of the terminal phalanges of the fingers and toes. Short metatarsals and metacarpals have not been described.
Other common imaging features include non-pneumatized mastoids (80%) and delayed fusion of the skull sutures (67%). The clavicles may be dysplastic (25%) with acroosteolysis of the acromial end. Less common features include Wormian bones (18%), mild scoliosis (12%), leg length discrepancy (8%), spondylolysis, spondylolisthesis, and narrow ilia. Coronal craniosynostosis has been reported in four individuals [Bertola et al 2010, Caracas et al 2012, Bizaoui et al 2019]. Chronic pain is reported in up to 60% of adults with pycnodysostosis, with onset usually in the third decade [Bizaoui et al 2019].
Bone fragility. Individuals with pycnodysostosis have an increased fracture rate with an average 0.2 fractures per year and an average age of first fracture around age ten years [Bizaoui et al 2019]. The youngest reported individual with a fracture was age ten months; This individual had two sibs who died, reportedly from the same disorder, suggesting a more severe phenotype or genotype; however, molecular studies were not performed [Caracas et al 2012].
Fracture healing is often delayed with incomplete remodeling. Surgical fixation is often complicated by narrow medullary canals, and sclerotic bone poses an increased risk of intraoperative iatrogenic fracture [Grewal et al 2019]. To date, no effective pharmaceutical treatments have been established for the bone fragility. Bisphosphonate therapy is contraindicated due to underlying osteoclast dysfunction in pycnodysostosis.
ENT. Stridor and laryngomalacia (20%) are not uncommon manifestations, and can lead to an early suspicion of pycnodysostosis. Obstructive sleep apnea (OSA) is frequently reported (>60%), and can be particularly severe in children with pycnodysostosis. Of those with OSA, 48% required noninvasive ventilation between ages five and ten years [Testani et al 2014, Bizaoui et al 2019]. Mild conductive hearing loss occurs in up to 50% of individuals [Bizaoui et al 2019].
Dental abnormalities include delayed eruption of the deciduous and permanent teeth, persistence of deciduous teeth (resulting in a double row of teeth), hypodontia, malocclusion, enamel hypoplasia, and increased caries [Turan 2014, Khoja et al 2015, Otaify et al 2018].
Nails are often flat, grooved, and dysplastic. The skin may be wrinkled over the dorsa of the fingers, secondary to shortened digits and acroosteolysis.
Neurologic. Intelligence is typically normal in affected individuals unless a brain malformation is present. Mild psychomotor difficulties have been reported in up to 30% of individuals [Bizaoui et al 2019]. Rarely reported neurologic abnormalities include Chiari malformation (1 individual), cerebral demyelination (3 individuals), and pyramidal syndrome (1 individual) [Soliman et al 2001, Stark & Savarirayan 2009, Bizaoui et al 2019].
Ocular abnormalities have been reported, including refractive disorders and strabismus. One individual was reported to have severe vision loss as a result of intracranial hypertension and papilledema [Bizaoui et al 2019].
Obesity has not been reported as a typical feature of pycnodysostosis; however, in a cohort of 27 individuals, 26% were found to be overweight [Bizaoui et al 2019].
Prognosis. Individuals with pycnodysostosis usually have normal life expectancy.
Other. Less commonly reported features include joint laxity, deformities of the chest shape (narrow chest, kyphosis, and lordosis), and hepatosplenomegaly. An ectopic pelvic kidney and unexplained pancytopenia have each been reported in one individual.
Genotype-Phenotype Correlations
No genotype-phenotype correlations for CTSK have been identified.
Nomenclature
The clinical features of pycnodysostosis (Greek: pycnos = dense; dys = defective; osteon= bone) were first described by Maroteaux and Lamy in 1962; hence, it is variably known as Maroteaux-Lamy syndrome [Xue et al 2011, Bizaoui et al 2019] (a term primarily used to refer to the unrelated condition, mucopolysaccharidosis type VI, caused by pathogenic variants in ARSB).
Pycnodysostosis is also sometimes referred to as "Toulouse-Lautrec syndrome," after the French artist Henri de Toulouse-Lautrec (1864-1901), who was retrospectively thought to have this condition based on several phenotypic features of the disorder including short stature, parental consanguinity, facial dysmorphism, frequent fractures, and large fontanels [Turan 2014] (see Figure 2).
Figure 2.
Prevalence
Approximately 200 affected individuals have been reported in the medical literature. Pycnodysostosis is estimated to affect about 1-1.7 individuals per million.
Differential Diagnosis
It is critical to distinguish pycnodysostosis from other primary sclerosing conditions of bone (see Table 3) characterized by osteopetrosis, since early hematopoietic stem cell transplantation may be a therapeutic option in some forms of osteopetrosis, whereas it would be of no benefit in individuals with pycnodysostosis, which rarely presents with bone marrow insufficiency [Bizaoui et al 2019].
Table 3.
Features of DiffDx Disorder Overlapping w/ Pycnodysostosis | Gene(s) | DiffDx Disorder | MOI | Features of DIffDx Disorder Not Observed in Pycnodysostosis |
---|---|---|---|---|
Osteosclerosis, diffuse & focal sclerosis of varying severity, modeling defects at metaphysis, osteomyelitis, pathologic fractures, tooth eruption defects | CA2 | Osteopetrosis w/renal tubular acidosis (OMIM 259730) | AR | Bone marrow impairment is rare; cranial nerve compression, DD, intracranial calcification, renal tubular acidosis |
CLCN7 SNX10 TCIRG1 | Osteopetrosis, severe neonatal or infantile forms (OMIM 611490, 615085, 259700) | AR | Cranial nerve compression (II, VII, VIII), extramedullary hematopoiesis, hydrocephalus, hypocalcemia, pancytopenia | |
CLCN7 PLEKHM1 TNFSF11 | Osteopetrosis, intermediate form 1 (OMIM 611497, 259710) | AR | Anemia, extramedullary hematopoiesis, occasional optic nerve compression | |
CLCN7 | Osteopetrosis, late onset form type 2 (OMIM 166600) | AD | Moderate hematologic failure, cranial nerve compression | |
FERMT3 | Osteopetrosis, moderate form w/defective leukocyte adhesion (OMIM 612840) | AR | Defective neutrophil adhesion to endothelial cells, hepatosplenomegaly, leukocytosis, mucosal bleeding | |
IKBKG | Osteopetrosis w/ectodermal dysplasia & immune defect (OMIM 300291) | XL | Anhidrotic ectodermal dysplasia, immunodeficiency (→ overwhelming infection), lymphedema | |
OSTM1 | Osteopetrosis, infantile form, w/nervous system involvement (OMIM 259720) | AR | Cranial nerve compression (II, VII, VIII), extramedullary hematopoiesis, hydrocephalus, hypocalcemia, pancytopenia, primary neurodegeneration incl retinal atrophy | |
TNFRSF11A | Osteopetrosis, infantile form, osteoclast-poor w/immunoglobulin deficiency (OMIM 612301) | AR | Anemia, hepatosplenomegaly, hypogammaglobulinemia, thrombocytopenia | |
Osteosclerosis, short stature, pathologic fractures | CSF1R TNFRSF11A SLC29A3 | Dysosteosclerosis (OMIM 618476) 2 | AR | Brain abnormalities, progressive neurologic deterioration (specific to CSF1R), patches of hyperpigmented skin, platyspondyly, radiolucency of widened submetaphyseal portions of tubular bones |
Osteosclerosis localized mainly to metaphyses & epiphyseal margins of appendicular bones & metaphyseal equivalents of axial bones | LRRK1 | Osteosclerotic metaphyseal dysplasia 3 | AR | DD; ↑ urinary pyridinoline & deoxypyridinoline excretion; ↑ serum alkaline phosphatase, aspartate aminotransferase & creatine kinase; seizures |
Acroosteolysis, joint laxity, short stature, skull deformities | NOTCH2 | Hajdu-Cheney syndrome (OMIM 102500) | AD | Mild ID (in a small proportion), osteoporosis |
Clavicular dysplasia, delayed anterior fontanelle closure, delayed eruption of teeth, high arched palate, short stature | RUNX2 | Cleidocranial dysplasia spectrum disorder | AD | Abnormally shaped pelvic & pubic bones, absent clavicles, thoracic deformations |
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Li et al [2019]
- 2.
Campeau et al [2012], Xue et al [2019]
- 3.
Iida et al [2016]
Secondary causes of bone sclerosis. Pycnodysostosis and other primary sclerosing conditions of bone caused by osteoclast dysfunction should be distinguished from the large number of secondary causes of bone sclerosis. Some alternative diagnoses to consider include fluorosis; beryllium, lead, and bismuth poisoning; myelofibrosis; Paget disease, sclerosing form (OMIM PS167250); and malignancies (lymphoma, osteoblastic cancer metastases) [Stark & Savarirayan 2009].
Management
There are no published treatment or surveillance guidelines for pycnodysostosis or standard guidelines on the best method or surgical intervention for fracture treatment in this condition. Management should emphasize multidisciplinary care and a considered approach to surgical intervention when appropriate.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with pycnodysostosis, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 4.
System/Concern | Evaluation | Comment |
---|---|---|
Constitutional |
| Consider referral to nutritionist if needed for weight management. |
Musculoskeletal | Complete radiographic skeletal survey incl lateral spine radiographs | |
Consider skull CT. | If clinical concern re craniosynostosis | |
Orthopedic consultation | Eval by specialist experienced in skeletal dysplasia if possible | |
ENT |
| |
Respiratory | Polysomnography | For all patients as early as practicable |
Dental | Baseline dental eval | |
Neurologic | Consider MRI. | If neurologic symptoms or concern re Chiari malformation |
Eyes | Baseline ophthalmologic exam | |
Genetic counseling | By genetics professionals 1 | To inform patients & families re nature, MOI, & implications of pycnodysostosis in order to facilitate medical & personal decision making |