Introduction: Pycnodysostosis is an extremely rare skeletal dysplasia caused by cathepsin K deficiency. It is characterized by extreme short stature with adult height (AH) in males typically less than 150 cm and in females less than 130 cm. Our objective was to evaluate the effect and safety of growth hormone (GH) treatment in 6 patients with pycnodysostosis treated according to the Dutch national pycnodysostosis guideline. Case Presentation: Six subjects (4 boys, 2 girls) presented with pycnodysostosis, treated with GH 1.4 mg/m2/day (∼0.046 mg/kg/day) for ≥1 year. Median (IQR) age at start of GH was 10.4 years (5.7; 12.2) and median height 113.5 cm (93.3; 129.3) (−4.2 SDS [−4.8; −3.6]). All children were prepubertal at start of GH. After 1 year of GH, median height gain was 7.6 cm (6.5; 8.5) (0.3 SDS [−0.3; 0.7]). Three children are still treated with GH, and the other three subjects reached AH: 1 boy reached an AH of 157.0 cm (−3.8 SDS) after 6.3 years of GH, and 2 girls reached an AH of 138.5 cm (−5.2 SDS) after 4.8 years of GH and 148.0 cm (−3.6 SDS) after 6.4 years of GH, respectively. This last girl received additional GnRH analogue treatment. In all subjects, height SDS remained stable or improved during and after GH treatment. No serious adverse advents were found. Serum IGF-I remained below the +2 SDS. Conclusion: Our data suggest that GH may prevent the decline in height which can be observed in children with pycnodysostosis. Further research is needed to confirm this. Also, the effect of other growth-promoting strategies such as treatment with an additional GnRH analogue warrants further investigation.

Established Facts

  • Pycnodysostosis is an extremely rare autosomal recessive skeletal dysplasia, characterized by extreme short stature and bone fragility.

  • Efficacy and safety data during growth hormone treatment are limited and heterogeneous.

Novel Insights

  • Our findings suggest that growth hormone treatment may prevent the decline in height SDS which can be observed in children with pycnodysostosis.

  • Growth hormone treatment with a dose of 1.4 mg/m2/day (∼0.046 mg/kg/day) appears to be safe without serious adverse events, while serum IGF-I concentrations remain within the reference range.

Pycnodysostosis (MIM 265800) is an extremely rare skeletal dysplasia with an estimated prevalence of 1–3 per million [1, 2]. The most common features described are severe short stature, bone fragility due to progressive osteosclerosis, acro-osteolysis of the distal phalanges, and skull deformities [3‒6]. The diagnosis of pycnodysostosis is based on clinical and radiological findings and/or identification of a biallelic pathogenic variant in the CTSK gene (MIM 601105) [7]. CTSK encodes cathepsin K, a lysosomal cysteine protease highly expressed in osteoclasts and involved in the resorption and remodeling of bone [8‒10].

In pycnodysostosis, the reported adult height (AH) in males is typically below 150 cm and in females below 130 cm, although a taller stature has also been described [1, 4, 7, 11]. Data on the effects of growth hormone (GH) treatment in children and adolescents with pycnodysostosis are limited and mainly consist of case reports. Soliman et al. [12] were the first to report improved linear growth after 1 year of GH treatment in 2 children with pycnodysostosis and GH deficiency (GHD). Case reports describing the effects of GH treatment often report short-term data and also include children diagnosed with (partial) GHD or multiple pituitary hormone deficiencies [12‒16]. In 2010, Rothenbuhler et al. [17] described 3 subjects with pycnodysostosis without GHD treated with GH during 12, 6.5, and 5 years who reached a markedly improved AH of −1.0, −0.5, and −1.0 standard deviation score (SDS), respectively. However, Doherty et al. [4] recently described only a modest, if any, increase in AH in 6 Danish patients with pycnodysostosis. Details on GH treatment were not reported. Furthermore, data on safety are scarce.

Based on the early data, a standardized, national GH treatment guideline for pycnodysostosis was introduced in The Netherlands with the aim to collect long-term follow-up data (online suppl. File 1; for all online suppl. material, see https://doi.org/10.1159/000539574). In summary, children diagnosed with pycnodysostosis, aged ≥4 years with a height <−3.0 SDS, were eligible for GH treatment with a dose of 1.4 mg/m2/day (∼0.046 mg/kg/day). Any underlying conditions such as hypothyroidism, metabolic disorders, or chromosomal defects were excluded. None of the children were GH deficient.

Since pycnodysostosis is an extremely rare disorder, the low number of patients makes it impossible to perform a randomized controlled trial to rigorously evaluate the efficacy and safety of GH treatment. However, valuable information can be obtained from observational studies. For that reason, we report short-term and long-term results of GH treatment in 6 subjects with pycnodysostosis.

Patients 1 and 2

Patient 1, a boy, the first child of consanguineous Moroccan parents, was diagnosed with pycnodysostosis shortly after birth. A pathogenic homozygous variant within CTSK (c.60_61insAG p.(Ile21Argfs*29)) was found. Medical history, prior to start of GH, showed G6PD deficiency, obstructive sleep apnea syndrome (OSAS) treated with continuous positive airway pressure, a fracture of the left and right tibia, a fracture of the left clavicle, and a left femur fracture (fracture rate 0.3 fractures/year). GH treatment was initiated at 11 years of age at a height of 125.9 cm (−3.7 SDS) (Fig. 1a; Table 1). During treatment, serum insulin-like growth factor (IGF)-I remained within the reference range (−2 to +2 SDS according to local immuno assays) (Table 1). Bone age assessment was performed yearly (Fig. 1a). BMI remained in the low-normal reference range. Polysomnography showed no worsening of OSAS. During GH treatment, he suffered a fracture of the right tibia and fractures of the left and right (2×) femur (fracture rate 0.6 fractures/year). At 18.0 years of age, AH was reached and GH treatment was stopped. His final height was 157 cm (−3.8 SDS) with a height gain of 27.0 cm during puberty [18‒20].

Fig. 1.

Growth charts of GH-treated subjects with pycnodysostosis. Individual growth charts of children with pycnodysostosis treated with GH 1.4 mg/m2/day (solid orange line = AH reached (a-c); dashed orange line = ongoing GH treatment (d-f)). Squares represent bone age. Target height is indicated by an ●. Fractures are indicated by an #. Start of estrogen treatment in patient C is indicated by an *. Growth charts according to Growth Analyzer 4.0. B, breast development; G, genital development; GH, growth hormone; GnRHa, gonadotrophin-releasing hormone analogue.

Fig. 1.

Growth charts of GH-treated subjects with pycnodysostosis. Individual growth charts of children with pycnodysostosis treated with GH 1.4 mg/m2/day (solid orange line = AH reached (a-c); dashed orange line = ongoing GH treatment (d-f)). Squares represent bone age. Target height is indicated by an ●. Fractures are indicated by an #. Start of estrogen treatment in patient C is indicated by an *. Growth charts according to Growth Analyzer 4.0. B, breast development; G, genital development; GH, growth hormone; GnRHa, gonadotrophin-releasing hormone analogue.

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Table 1.

Patient characteristics

P1P2P3P4P5P6
Gender 
Gestational age, week 41 36 40 40 40 41 
Birth weight SDS −3.5 −2.6 −0.3 −1.9 −1.3 −1.8 
Birth length SDS NA −1.4 NA NA NA −2.5 
Target height SDS −0.5 −0.5 −1.1 −1.3 −0.1 −0.6 
At start of GH treatment 
 Age, years 11 11 13 
 Height, cm 125.9 111.2 115.8 139.3 88.2 95.0 
 Height SDS −3.7 −4.6 −5.3 −3.3 −4.2 −4.2 
 BMI SDS −0.8 1.0 0.6 0.0 −0.2 −1.7 
 SH/H SDS 1.8 4.4 4.0 NA 2.7 0.2 
 IGF-I SDS 0.4 0.9 −1.9 −0.9 0.2 0.6 
 IGFBP3 SDS −1.0 −0.6 −0.5 NA 0.0 0.2 
Start puberty 
 Age, years 12.6 10.8 11.9 13.9 
 Height, cm 130 121.6 121.8 141.3 
 Height SDS −3.5 −4.1 −5.0 −3.4 
 BMI SDS −1.9 0.2 1.6 0.0   
Start puberty – AH 
 Duration of GH, years 6.3 4.8 6.4 
 Pubertal height gain, cm 27.0 16.9 26.2 
AH 
 Height, cm 157.0 138.5 148.0 
 Height SDS −3.8 −5.2 −3.6 
 Height gain start GH – AH, cm 31.1 27.3 32.5 
 Height gain SDS start GH – AH −0.1 −0.6 1.7 
 BMI SDS −2.4 0.9 3.3    
P1P2P3P4P5P6
Gender 
Gestational age, week 41 36 40 40 40 41 
Birth weight SDS −3.5 −2.6 −0.3 −1.9 −1.3 −1.8 
Birth length SDS NA −1.4 NA NA NA −2.5 
Target height SDS −0.5 −0.5 −1.1 −1.3 −0.1 −0.6 
At start of GH treatment 
 Age, years 11 11 13 
 Height, cm 125.9 111.2 115.8 139.3 88.2 95.0 
 Height SDS −3.7 −4.6 −5.3 −3.3 −4.2 −4.2 
 BMI SDS −0.8 1.0 0.6 0.0 −0.2 −1.7 
 SH/H SDS 1.8 4.4 4.0 NA 2.7 0.2 
 IGF-I SDS 0.4 0.9 −1.9 −0.9 0.2 0.6 
 IGFBP3 SDS −1.0 −0.6 −0.5 NA 0.0 0.2 
Start puberty 
 Age, years 12.6 10.8 11.9 13.9 
 Height, cm 130 121.6 121.8 141.3 
 Height SDS −3.5 −4.1 −5.0 −3.4 
 BMI SDS −1.9 0.2 1.6 0.0   
Start puberty – AH 
 Duration of GH, years 6.3 4.8 6.4 
 Pubertal height gain, cm 27.0 16.9 26.2 
AH 
 Height, cm 157.0 138.5 148.0 
 Height SDS −3.8 −5.2 −3.6 
 Height gain start GH – AH, cm 31.1 27.3 32.5 
 Height gain SDS start GH – AH −0.1 −0.6 1.7 
 BMI SDS −2.4 0.9 3.3    

AH, adult height; F, female; GH, growth hormone; H, height; IGF, insulin-like growth factor; IGFBP3, IGF binding protein 3; M, male; NA, not available; SDS, standard deviation score; SH, sitting height; P, patient.

Subject 2 (P2), sister of patient 1, was also diagnosed with pycnodysostosis shortly after birth with the same homozygous pathogenic CTSK variant. Medical history, prior to start of GH, showed OSAS treated with a nasopharyngeal tube, and a fracture of the left and right tibia (fracture rate 0.2 fractures/year). At 9 years of age, GH was started at a height of 111.2 cm (−4.6 SDS) (Fig. 1b). Serum IGF-I fluctuated around 2 SDS during GH treatment. BMI remained in the normal-high reference range. Polysomnography showed no worsening of OSAS. She developed pseudoarthrosis of the right tibia for which she was operated twice and suffered a fracture of the left tibia (fracture rate 0.2 fractures/year). At 14.3 years of age, AH was reached and GH treatment was stopped. Her final height was 138.5 cm (−5.2 SDS), and height gain during puberty was 16.9 cm.

Patient 3

Patient 3, a girl, was diagnosed with pycnodysostosis shortly after birth because of dysmorphic features and a positive family history. She is the second child of consanguineous Moroccan parents. A homozygous pathogenic missense variant was found in CTSK (c.436G>C p.(Gly146Arg)). Medical history prior to start of GH showed fractures of the distal phalanx of the fifth digit, fractures of the left and right (2×) tibia, a left forearm fracture, and a fracture of the right third metatarsal (fracture rate 0.6 fractures/year). GH was started at 11 years of age at a height of 115.8 cm (−5.3 SDS) (Fig. 1c). During treatment, serum IGF-I fluctuated between 1 and 2 SDS. She was 11.9 years at start of puberty with a height of 120.7 cm (−5.0 SDS). At the discretion of the treating physician and parents, a gonadotrophin-releasing hormone analogue (GnRHa) was started to postpone puberty. After approximately 2 years of combined GH and GnRHa treatment, height gain slowed and the patient wanted breast development to start similar to her peers. Therefore, estrogen replacement was started in a low dose (6.25 μg). During the ∼3.5 years of combined GH, GnRHa, and estrogen treatment, BMI increased from 0 SDS to 2.4 SDS. Her BMI at AH was 3.3 SDS. She had suffered fractures of the left and right tibia, the left third metatarsal, and left femur (fracture rate 0.6 fractures/year). GH treatment was stopped at 17.8 years of age. Her AH was 148.0 cm (−3.6 SDS). Height gain from start of puberty until AH was 26.2 cm, including the period of combined GH, GnRHa, and estrogen treatment.

Patient 3 has two older family members with pycnodysostosis who had not been treated with GH because this was not approved as an indication for GH treatment in The Netherlands at that point in time. The first family member was her older brother who reached an AH of 143.0 cm (−5.8 SDS) (Fig. 2a). The second family member was her cousin (♀) who reached an AH of 148.0 cm (−3.6 SDS) (Fig. 2b).

Fig. 2.

a, b Growth charts of untreated subjects with pycnodysostosis. Individual growth charts of children with pycnodysostosis not treated with GH, family members of subject 3. Target height is indicated by an ●. Growth charts according to Growth Analyzer 4.0.

Fig. 2.

a, b Growth charts of untreated subjects with pycnodysostosis. Individual growth charts of children with pycnodysostosis not treated with GH, family members of subject 3. Target height is indicated by an ●. Growth charts according to Growth Analyzer 4.0.

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Patient 4

Patient 4 is a boy of Moroccan descent of consanguineous parents who was diagnosed with pycnodysostosis at 2 years of age because of short stature. Molecular analysis showed a homozygous pathogenic missense variant in CTSK (c.436G>C p.(Gly146Arg)). Medical history prior to start of GH showed fractures of the right (3×) and left (2×) tibia and a fracture of the left fifth metatarsal (fracture rate 0.4 fractures/year). At 13 years of age, with a height of 139.3 cm (−3.3 SDS), GH treatment was initiated (Fig. 1d). Shortly after start of GH, puberty started. During treatment, serum IGF-I concentrations fluctuated between 1 and 2 SDS. BMI remained around 0 SDS. He suffered no additional fractures since start of GH (fracture rate 0 fractures/year). At 15.7 years of age, he is still being treated with GH. Height gain after 2 years of GH was 11.5 cm, and height SDS is currently −3.6 SDS.

Patients 5 and 6

Patient 5, a boy of Curacao descent of non-consanguineous parents, was diagnosed with pycnodysostosis shortly after birth because of dysmorphic features. A homozygous pathogenic variant was found in CTSK (c.891-1_891delinsAT (p.?)). Medical history showed a fracture of the right clavicle (fracture rate 0.3 fractures/year). He started GH treatment at 4 years of age with a height of 88.2 cm (−4.2 SDS) (Fig. 1e). Between 6 and 7.5 years of age, the subject was non-compliant. During treatment, serum IGF-I fluctuated between 0 and 1 SDS. BMI remained around 0 SDS. He suffered fractures of the left (3×) and right tibia (3×) (fracture rate 0.7 fractures/year). Currently, at age 11.5 years, he is still being treated with GH: height gain after 7.5 years of GH treatment (note: 6 years’ compliant) is 40.3 cm, and height SDS is −3.5 SDS.

Patient 6, cousin of patient 5, was diagnosed with pycnodysostosis at 2 years of age because of short stature with the same pathogenic CTSK variant. Medical history prior to start of GH showed no abnormalities. GH treatment was started at 5 years of age with a height of 95.0 cm (−4.2 SDS) (Fig. 1f). During treatment, serum IGF-I remained within the reference range. BMI increased from −1.7 SDS to −0.7 SDS. A routine X-ray to assess skeletal maturation, 5 months after the start of treatment, showed a pathological fracture of the distal phalanx of the fifth digit as an incidental finding (fracture rate cannot be calculated). At age 6.4 years, he is still being treated with GH. Height gain after approximately 1 year of GH is 7.3 cm, and height SDS is −3.9 SDS.

We present short-term and longer term effects of GH treatment in 6 children with pycnodysostosis, an extremely rare skeletal dysplasia. All children were treated according to a standardized, national GH treatment guideline. The findings add to the limited data currently available on the effect and safety of GH treatment in children with pycnodysostosis. Our data suggest that GH treatment has a modest effect on linear growth and may prevent the decline in height SDS which can be observed.

Pycnodysostosis is typically characterized by severe short stature [1, 4, 11]. Indeed, all our subjects were severely short at start of GH treatment (i.e., <−3 SDS). However, height SDS varied considerably (−3.3 to −5.3 SDS) and not all subjects were (severely) short during infancy/preschool years. This has also been described by Doherty et al. [4] who reported 2 children aged 5 and 7 years with a height of −0.8 SDS. No genotype-phenotype correlations have been reported despite phenotypical variability [5]. The natural growth course in pycnodysostosis is not well studied. In practice, a progressive decline in height SDS is observed, with a blunted pubertal growth spurt. This growth pattern is comparable to other skeletal dysplasias [21, 22]. Until now, treatment with GH is the only available treatment option for improving height in subjects with pycnodysostosis. However, data on the effects of GH treatment are not only scarce but also heterogenous including patients with and without (partial) GHD and receiving GH treatment with variable dosages and durations [1, 4, 12‒17]. Hence, there is a need for more data.

We observed a median height gain of 7.6 cm (range 6.4–8.4) after 1 year of GH treatment in 6 prepubertal subjects without GHD. These results are comparable to the median height gain of 9.4 cm/year in 4 subjects described by Soliman et al. [16], albeit slightly less. However, in contrast to our patients, the patients described by Soliman et al. [12] were also diagnosed with GHD and that could account for the slightly higher height gain. GHD has been described in several subjects with pycnodysostosis [13‒16] possibly due to an increased bone volume of the sellar wall that might increase intrasellar pressure which could impair portal blood flow, resulting in hypopituitarism [23]. None of our subjects were suspected to be GH deficient based on clinical and laboratory parameters such as growth pattern, IGF-I and IGFBP-3 concentrations, and bone age.

Three of our subjects reached AH. All subjects were prepubertal, but relatively old at start of GH, i.e., ≥9 years of age. In these 3 GH-treated subjects, height gain during puberty was comparable to the average normal pubertal height gain of 20 cm in girls and 30 cm in boys [18, 24] (Table 1). This is remarkable since the pubertal height gain in children with pycnodysostosis is expected to be very poor. Although AH was below the −2 SDS and subjects did not reach a near-normal stature as described by Rothenbühler et al. [17], AH was higher than the average of <150 cm described in men and <130 cm described in women. The difference in response to GH between the individuals described by Rothenbühler et al. [17] and our subjects might partly be explained by the relatively older age at start of GH in our subjects. Also, the dosage we used (1.4 mg/m2/day) was lower compared to 2 out of the 3 subjects described by Rothenbühler et al. [17] (mean GH dose of 3.6, 2.0, and 0.9 mg/m2/day). Parental height and height SDS at start of GH treatment were comparable with our subjects.

GH treatment with additional GnRHa for ∼3.5 years resulted in an AH of 148 cm in subject 3. This is almost 10 cm taller than subject 2 who was treated with GH alone and 5 cm taller than her untreated brother. Our finding suggests that GnRHa in addition to GH might improve height gain in children with pycnodysostosis who are still short at onset of puberty. Her untreated niece also reached an AH of 148 cm; however, with regard to height SDS she was less affected and has always been taller than subject 3. No model is known to predict AH accurately at start of puberty, particularly for children with a skeletal dysplasia such as pycnodysostosis. Therefore, further research is needed to determine whether adjunctive GnRHa treatment might improve AH.

No serious adverse events were reported during GH treatment. Serum IGF-I remained within the reference range without adaptation of the GH dose. BMI remained stable in 5/6 subjects. In subject 3, BMI increased substantially during combined GH, GnRHa, and estrogen treatment. Although we cannot exclude a possible role of GH, other factors are more likely involved such as lifestyle and GnRHa treatment [25]. Fractures of long bones after minor trauma are common in subjects with pycnodysostosis [17, 26]. After start of GH, we did not observe an evident decrease nor increase in fractures. However, this study is not suitable to accurately assess the effect of GH treatment on fracture rate due to the i.a. variable age of first fracture, age at start of GH treatment, and duration of GH treatment. Further research is needed on the effect of GH treatment on fracture rate in this group of patients.

Our results must be considered in the light of some limitations. First, the number of patients is small. Since pycnodysostosis is an extremely rare disorder, this is unavoidable. Second, to reliably evaluate the effects of GH, a randomized controlled trial is normally needed but since pycnodysostosis is so rare this is currently not feasible. Also, 1 subject received additional GnRHa treatment, which results in a more complex interpretation of GH efficacy itself. It is important to follow these children and adolescents to obtain further longitudinal data. Ideally, extensive international collaborations to generate larger study groups would facilitate research to establish effective and safe treatments for this disorder.

In conclusion, pycnodysostosis is an extremely rare disorder for which there is currently no cure. Data on the effects of GH treatment on height are very limited and heterogenous. To our knowledge, this is the first group of children with pycnodysostosis who were treated according to a standardized, national GH treatment protocol. Our data suggest that GH may prevent the decline in height SDS which can be observed in children with pycnodysostosis. Further research is needed to confirm this. The effects of other growth-promoting strategies such as combined treatment with GH and a GnRH analogue also warrant further research.

Ethical approval is not required for this study in accordance with national guidelines. Written informed consent was obtained from the parent/legal guardian of the patients for publication of the details of their medical case and any accompanying images.

There is nothing to disclose for this study.

No funding was received for this study.

Judith S. Renes made substantial contributions to the acquisition, analysis, and interpretation of data and drafted the work. Theo C.J. Sas, Agnes Clement-de Boers, Nitash Zwaveling-Soonawala, Sabine E. Hannema, Janiëlle A.E.M. van der Velden, and Danielle C.M. van der Kaay made substantial contributions to the acquisition and interpretation of data and critically reviewed the work. Anita C.S. Hokken-Koelega made substantial contributions to the design of the work and interpretation of data and critically reviewed the work. All authors approved the final version.

All data generated and analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

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