Expanding the Phenotypic Spectrum of Kenny-Caffey Syndrome

Abstract

Context: Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish.

Objective: The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders.

Methods: We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers.

Results: Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common.

Conclusion: Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

Keywords: Sanjad–Sakati syndrome; chronic kidney disease; gracile bone dysplasia; hypoparathyroidism retardation dysmorphism; osteocraniostenosis.

Figure 1.

Variants Kenny–Caffey syndrome patients. (A) Top: TBCE is involved in αβ-tubulin dimer formation and dissociation (5-7). KCS1/SSS patient pathogenic variants are located to the CAP-Gly domain that binds the tubulin α-subunit. The vast majority of patients carry the homozygous c.155-166del12 (p.Ser52_Gly55del) pathogenic variant. Bottom: FAM111A is involved in DNA replication (8, 9) and anti-viral defense (10-12). KCS2 and GCLEB (italics) variants in FAM111A show clustering in and around the serine peptidase domain and autocleavage site (scissors). (Likely) pathogenic variants from our case series are shown in bold text. CAP-Gly, cytoskeleton-associated protein-glycine-rich, PIP, PCNA-interacting protein, U1, domain of unknown significance, UBL, ubiquitin-like. *Compound heterozygous variants that were found together in 1 GCLEB patient. (B) Pedigrees of KCS2 patients, indicating patients with symbols partially filled in with black based on their phenotypes. The question mark indicates the person is likely affected but the phenotype is unknown. Probands are indicated with arrows. CKD, chronic kidney disease; nt, not genetically tested; wt, wild type.

Figure 2.

Screening for KCS1 and KCS2 case reports. Flow scheme detailing the screening methods used according to the PRISMA 2020 guidelines (25).

Figure 3.

CKD progression. Progression of CKD shown as eGFR for age for patient (A) F5-I-1 and (B) F5-II-4. The dashed line represents the healthy (A) male and (B) female population (33).

Figure 4.

Laboratory values KCS1 and KCS2 patients. Measurements of serum (A) total calcium, (B) phosphorus, (C) magnesium, (D) parathyroid hormone, and (E) 25-hydroxy vitamin D in KCS1 and KCS2 patients reported in literature, before the start of treatment, and (F) measurements of urine calcium:creatinine ratio. Squares represent patients older than 10 days (calcium), 2 months (phosphorus) or 7 years (calcium:creatinine), triangles younger than 10 days (calcium), 2 months (phosphorus) or 7 years (calcium:creatinine), and diamonds exact age unknown. Circles are used when age is not specified. Values related to the growth axis with (G) peak growth hormone and (H) IGF-1 levels (in SD: standard deviation from the mean). In addition, (I) glucose and (J) ALP levels where squares represent individuals with high ALP for age. Measurements related to thyroid functioning with (K) TSH and (L) FT4 levels. The indicated areas represent the reference range (age-dependent for calcium, phosphorus and calcium creatinine). For PTH, values below the detection limit were included as 0 pmol/L. ***P < .001.