The older sister, an 11-year-old girl whose height was 130.6 cm (-2.28 standard deviation score [SDS]) (case 1), was born at 37⁺¹ weeks of gestation weighing 2,200 g (-1.58 SDS) and was small for gestational age (SGA) after an uneventful pregnancy. No perinatal problems, except microcephaly and ventriculomegaly, were recorded. On physical examination, her head circumference was 47 cm (<-3 SDS), and she had unique craniofacial features including a bird-headed appearance with a receding forehead, micrognathia, and a large beaked nose. Her Tanner stage was 3, and her bone age was the same as her chronological age. Her predicted adult height (PAH) as measured using the Bayley-Pinneau (BP) method was 148 cm. Her karyotype was 46, XX (normal female). Endocrine tests were performed, and her hormone levels were within normal ranges (Table 1). There were no abnormal brain magnetic resonance imaging (MRI) findings. She was started on recombinant human growth hormone (rhGH) treatment at 11 years of age due to no postnatal catch-up growth. Two years after the start of treatment, her scoliosis was aggravated, and she was prescribed a brace. She continued rhGH treatment until she was 15 years old (approximately 4 years into rhGH therapy). At the age of 18 years, her adult height had reached 148.9 cm (-2.47 SDS) (Fig. 1A). She displayed mild cognitive and behavioral disorders during the treatment, for which we consulted colleagues from the department of psychiatry. Her cognitive and intellectual function tests revealed a full-scale intelligence quotient of 80–89 according to the Korean Wechsler Adult Intelligence Scale-IV for her age. In the comprehensive attention test, a decrease in interference in attention and divided attention was observed.

The younger sister, a 6-year-old girl whose height was 108.7 cm (-1.66 SDS) (case 2), was born at 37 weeks of gestation, weighing 2,100 g (-1.61 SDS); she was SGA without other medical problems except microcephaly. On physical examination, she had a small head circumference of 43 cm (<-3 SDS), and both breasts were engorged to Tanner stage II–III. Her bone age was advanced by more than 4 years. Her PAH as measured using the BP method was less than 140 cm. She presented with clinical characteristics similar to those of case 1, including a bird-shaped head with microcephaly, micrognathia, and a large beaked nose. Her karyotype was also 46, XX (normal female). Following endocrine tests, she was diagnosed with CPP and subclinical hypothyroidism (Tables 1, 2). Additionally, brain examination by MRI revealed a HH of a pedunculated nonenhancing mass in the tuber cinereum that extended into the suprasellar cistern (Fig. 2A, B). She received a depot gonadotropin-releasing hormone agonist (GnRHa) with rhGH treatment at 6 years of age for 4 years and 6 months for CPP and growth impairment and also began 50 μg of concurrent levothyroxine. When she was 11 years old, she slipped on the stairs and was diagnosed with a right-slipped capital femoral epiphysis (SCFE). She underwent surgery for fixation of the right femur head and prophylactic screw fixation of the left capital femoral epiphysis concurrently (Fig. 3A, B). After the surgery, she stopped rhGH and GnRHa and only continued treatment with levothyroxine for hypothyroidism. At the age of 13 years, she experienced menarche. Her height was 144.3 cm (-2.0 SDS) with a bone age of 15 years (Fig. 1B). We followed her HH size using MRI and found no significant interval change (Fig. 2C). She also showed mild cognitive and behavioral disorders and planned to undergo a test to evaluate her attention and behavioral problems.

Their parents were healthy and nonconsanguineous. Their mother’s height was 168 cm (+1.41 SDS), and their father’s height was 174 cm (+0.16 SDS). There was no family history of dwarfism, dysmorphic facial features, or developmental delay. Due to the presence of characteristic facial and cranial features, SGA without catch-up growth, HH, SCFE, and behavioral psychiatric problems, we suspected an underlying genetic cause. To identify this, whole exome sequencing was performed and identified 2 compound heterozygous pathogenic variants of the CEP152 gene (c.2034T>G, p. Tyr678Ter* and c.314G>A, p.Trp105Ter*). These variants were inherited from their parents, which was confirmed by Sanger sequencing. SCKL 5 follows an autosomal recessive inheritance pattern, in which genetic disorders occur when an individual inherits 2 nonworking genes for the same trait (one from each parent), and the variant may be either compound heterozygous or homozygous. If an individual receives one working gene and one nonworking gene, the person will be a carrier for the disease but will usually not show symptoms. Thus, their parents were carriers of each variant with no symptoms of SCKL 5. The variant c.2034T>G in CEP152 creates a stop codon at position 678 on the exon, and the variant c. 314G>A creates a stop codon at position 105 on the exon. These variants have been reported to occur at extremely low frequencies in large population cohorts (GenomAD). Both variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics [7] and were suspected to cause SCKL 5 with an autosomal recessive inheritance pattern (Fig. 4A, B).

The study was approved by the Institutional Review Board of Inha University Hospital (No. 2022-02-023-000). The images were published with the consent of the patients and their legal guardians.

Independent informed consent for publication of this case report was also obtained.