Ophthalmologic Impairment and Intellectual Disability in a Girl Presenting Kenny-Caffey Syndrome Type 2

Abstract

Kenny-Caffey syndrome (KCS) is a rare genetic condition characterized by growth retardation, bone abnormalities, and hypoparathyroidism. Herein, we report an unusual case of a 10-year-old girl with Kenny-Caffey syndrome type 2 (KCS2) presenting with vision impairment-suspected maculopathy and intellectual disability. Endocrine evaluation showed low calcium and high phosphorus plasma levels. Radiographic evaluation revealed short metacarpal bones and delayed bone age. Sequencing analysis showed a missense variant in FAM111A (R569H), unidentified in her parents. Better understanding of potential neurological and ophthalmological findings in KCS2 patients is important to improve quality of life of these patients as usually they exhibit long survival.

Introduction

Kenny-Caffey syndrome (KCS) is a rare genetic condition that was originally described by Kenny and Linarelli in 1966. ¹ Later, Caffey reported its radiologic findings in 1967. ² KCS is clinically characterized by growth retardation, delay in bone maturation, cortical thickening of the long bones and medullary stenosis, delayed closure of fontanelle, ophthalmic and dental abnormalities, hypocalcemia secondary to hypoparathyroidism, and convulsion associated with hypocalcemia. ^{1 3 4 5} KCS is classified according to clinical features and mode of inheritance into two types: Kenny-Caffey syndrome type 1 (KCS1) is characterized by delays in cognitive development, while Kenny-Caffey syndrome type 2 (KCS2) manifests classically with a normal intelligence. ³

As for their pattern of inheritance, KCS1 (OMIM 244460) is classified as an autosomal recessive syndrome and is associated with homozygous or compound heterozygous variants in TBCE . ^{3 6} KCS2 (OMIM 127000), on the other hand, is autosomal dominant due to heterozygous variants in FAM111A , a gene that seems crucial for parathyroid hormone regulation, calcium homeostasis, and normal bone and growth development. ^{3 5 7}

We report a female patient with a hotspot variant in FAM111A . Her clinical findings are unusual in that it include ophthalmologic manifestations and global developmental delays.

Case Report

The patient is a 10-year-old girl with short stature of unknown cause born to nonconsanguineous parents. The child was born at 39 weeks and 5 days of gestation, weighing 2,950 g (−0.9SD), measuring 47 cm (−0.98SD), with head circumference of 33 cm (−1.22SD). Apgar scores at first and fifth minutes were 7 and 8, respectively. Her neonatal screening was unremarkable. At the age of 1 year, the patient was hospitalized due to pneumonia. Later on, she had several hospitalizations due to asthma.

Her neuropsychomotor development was delayed. She sat without support at 1 year, walked unsupported at 2 years, spoke the first meaningful words at 3 years, and used diapers up to 3 years. Short stature was noted at 6 years. Thyroid function tests were normal. Abdominal ultrasound and echocardiography did not reveal abnormalities. Endocrinologic evaluation showed low calcium and high phosphorus plasma levels as well as borderline parathyroid hormone. Radiographic evaluation disclosed a probable old right distal humerus fracture, mild diffuse bone thinning of spine, short metacarpal bones, and delay of bone age. The evaluation of the pelvis was normal ( Figs. 1 and 2 ). There were no abnormalities in the skull and face ( Fig. 3A, B ). Skull computed tomography scan revealed calcification of the basal nuclei ( Fig. 3C ). Dental assessment did not reveal any abnormalities ( Table 1 ). She presented with visual impairment, especially in her left eye. She has been wearing glasses since she was 7 years old. Ophthalmological evaluation disclosed a 0/6 papillae, with slightly blurred edges and turgid vessels at fundus. The chambers of both eyes were shallow, and the left eye showed moderate pigmentation irregularity of macula. The child was diagnosed with bilateral high hyperopia (a grade of +8 diopters on the right eye and +10 diopters on the left) and a probable maculopathy. Subsequently, she lost follow-up with the ophthalmology from the hospital.

Fig. 1.

Hands of the patient ( A, B ) and her respective radiographies ( C, D ). Note especially the short metacarpal bones.

Fig. 2.

Spine ( A ) and pelvis ( B ) radiographies. Mild diffuse bone thinning can be observed on spine ( A ).

Fig. 3.

Skull radiographies of the patient did not show abnormalities ( A, B ). However, the computed tomography scan revealed calcification of the base nuclei ( C ).

Table 1. Comparison of the clinical findings verified in our patient with those found in Kenny-Caffey syndrome type 1 (KCS1) and 2 (KCS2).

Clinical findings	KCS1 (%)	KCS2 (%)	Patient
Pattern of inheritance	AR	AD	AD
Short stature	96	93	+
Mental/Neuropsychomotor retardation	82	16	+
Congenital hypoparathyroidism	90	73
Delayed bone age	65	50	+
Intrauterine growth retardation	83	36
Hypocalcemia	92	86	+
Symptomatic hypocalcemia	87	83	+
Anemia	57	54
Microcephaly	87	8
Relative macrocephaly	15	92
Delayed closure of anterior fontanel	17	92
Absent diploic space in calvaria	74	74
Prominent forehead	89	94
Microphthalmia	64	70
Hyperopia	39	77	+
Strabismus	17	23
Maculopathy		?	+
Dental anomalies	85	80
Micrognathia	77	62	+
Cortical thickening and medullary stenosis of long bones	86	87

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ?, unknown.

Note: Based on Moussaid et al. ⁶

On physical examination, performed at 10 years and 4 months of age, the stature was 100 cm (−6.38SD), weight of 18 kg (−4.32SD), and head circumference of 48.5 cm (−3.38SD). She also presented upslanting palpebral fissures, micrognathia, thin nose, and increased space between 1st and 2nd toes ( Figs. 1 and 4 ; Table 1 ). Her Wechsler Intelligence Scale for Children (WISC III) showed lower average of the overall intellectual performance. Furthermore, execution and perceptual organization was borderline, while the processing speed was intellectually deficient.

Fig. 4.

Facial appearance of the patient at 10 years and 4 months showing thin nose and micrognathia ( A, B ).

High resolution GTG-Banding karyotype was normal (46,XX). DNA was isolated by salting-out method from both patient and parents blood samples. The entire coding sequence and exon–intron boundaries of FAM111A gene were amplified by conventional polymerase chain reaction (PCR) using primers designed with Primer3 program ( http://frodo.wi.mit.edu/primer3/ ). Amplification reactions were performed in a final volume of 25 μL containing 0.4 mmol/L of dNTPs (deoxyribonucleotide triphosphates), 1.5 mmol/L of MgCl ₂ , 0.4 μmol/L of each primer, 1 U of Platinum Taq DNA polymerase, and 100 ng of genomic DNA. Samples were denatured at 94°C for 5 minutes, followed by 35 cycles of 94°C for 30 seconds, 52 to 56°C for 30 seconds, and 72°C for 30 seconds, with a final extension at 72°C for 5 minutes. The PCR products were purified with ExoSAP-IT kit by incubation for 15 minutes at 37°C and 15 minutes at 80°C. Sanger sequencing was performed using automatic sequencer ABI-PRISM 3130 Genetic Analyzer and resulting electropherograms analyzed with Chromas Lite program. Sequencing analysis of the patient showed a missense variant in exon 5 (c.1706 G > A) ( Fig. 5 ), resulting in amino acid substitution (R569H). None of the parents had this alteration, indicating that the variant occurred de novo.

Fig. 5.

Sanger sequencing electropherograms of the patient and her parents. FAM111A variant found in the patient (R569H) is showed. Heterozygous peak is justified by the autosomal dominant pattern of inheritance associated with the syndrome.

Discussion

KCS is characterized clinically by the presence of multisystemic findings. ^{1 4 7 8 9 10 11 12} Clinical characteristics along with a variant in FAM111A confirmed her diagnosis of KCS2. Unger et al reported this same variant in 2013, where they observed for the first time its association with KCS (four of five patients had the variant). ⁷ Later, another group also reported this variant in four isolated cases diagnosed with KCS2. ³

FAM111A is located in the long arm of chromosome 11 (11q12.1) and encodes a protein that has a C-terminal region homologous to trypsin-like peptidases. FAM111A was shown to have an important role in viral infections due to its interaction with SV40 large T antigen, where the gene restricts the host range function and helps the virus survival and replication. ¹³

Although the variant found in our patient is considered a hotspot mutation of KCS2, the prediction of a possible impact of it by PolyPhen suggests that R569H is a benign amino acid substitution for the individual's genome. ^{3 7} In silico analyses also showed that this de novo variant would not significantly affect protein function. ^{7 14} We performed a three-dimensional protein model to obtain an insight on the consequences of the altered amino acid within protein structure. As shown in Fig. 6 , the difference between wild type (WT) and altered proteins lies in shape and size: the altered one is shorter and more cyclic than the WT. Unger et al showed that R569H is located close to an area of the protein that would be well positioned to perform interactions with other molecules. ⁷ The difference in size and structure caused by the altered amino acid could adversely affect the intermolecular bindings with physiological partners, which could lead to the phenotype of KCS2. The hypothesis that R569H variant prevents or weakens intermolecular interactions of FAM111A and consequently increases the gene activity could be observed in heterozygosity and would explain the singular phenotype of KCS2 despite the supposed lack of damage of this variant. ^{7 13} However, as the gene function remains unclear as well as the protein regulatory pathways, future research in FAM111A is still needed to elucidate such intriguing questions.

Fig. 6.

Three-dimensional protein model showing the difference in structure between both wild type and altered proteins.

Major differential diagnoses of KCS2 include osteocraniostenosis (OMIM 602361), 22q11.2 deletion syndrome (velocardiofacial/DiGeorge) (OMIM 192430/188400), and hypoparathyroidism-retardation-dysmorphism syndrome/Sanjad-Sakati syndrome (OMIM 241410). ^{4 6 7 15} All of them present in their phenotypic spectrum short stature, parathyroid dysfunction, hypocalcemia, and ocular alterations. Osteocraniostenosis is also caused by mutations in FAM111A , which is characterized by bone alterations, such as cranial suture dysfunction, defective dentition, spinal cord stenosis, and small bones.

Many studies that describe the clinical characteristics of patients with KCS are prior to the discovery of the related genes and, consequently, of the classification of the syndrome into different types. Therefore, there is a certain difficulty in establishing a proper genotype–phenotype correlation.

Growth retardation is a common feature in KCS and usually starts at the prenatal period. ⁹ Growth hormone (GH) treatment seems to play a limited role in the management of these patients, even with KCS2. ^{8 9 14 16} However, a study performed an evaluation of the use of GH in five patients with KCS and four of them showed a normal response. ¹⁷ Moreover, another study reported a patient who underwent treatment with GH therapy (0.5 IU/kg/wk) at 7 years and 5 months of age. ¹⁶ The authors observed that after 2 years the height standard deviation for her chronological age improved from −5.4SD to −4.4SD. They suggested that a combined use of vitamin D, magnesium, and GH could perhaps be effective for treating the short stature in these individuals. As observed in Fig. 7 , our patient used GH during a year (from 11 to 12 years old). We are not sure if this treatment had some effect. However, growth curve seemed to change before and after the treatment with GH.

Fig. 7.

Growth chart associating the growth presented by the patient and the use of some medicines. Growth hormone was used for approximately 1 year, from 11 to 12 years. The patient was also treated with calcitriol from 10 years and 6 months to 15 years, and calcium carbonate and vitamin D for a similar period (it only extended a little further until 15 years and 6 months).

As for the bone alterations associated with KCS, cortical thickening, medullary stenosis of tubular bones, and delayed closure of the anterior fontanelle are common features. ^{1 8 9 10 11 12 18 19 20} Polysyndactyly was rarely described. ³

Regarding craniofacial findings, macrocephaly, facial hypoplasia, prominent forehead, micrognathia, and dental anomalies have been reported in KCS. ^{4 9 11 20} These dental anomalies consist of microdontia, especially involving the lower incisors and canines, and oligodontia. ^{5 6}

Ophthalmological manifestations include microphthalmia, nanophthalmia, esotropia, and refractive defects (myopia, hypermetropia). ^{1 4 9 10 11 12} However, these findings can be quite diverse. In our review, we found only two reports of patients presenting a macular abnormality with KCS. ²¹ The first was a girl that had the macular area of both eyes described as grayish. It was deeply pigmented and poorly defined, giving an aspect of macular crowding. Her intelligence was normal, which suggests the diagnosis of KCS2. ²¹ The second report was of two boys presenting KCS with an ellipsoid macular fold horizontally directed affecting the fovea. ²² Other ophthalmologic abnormalities rarely found are tortuous retinal vessels, bilateral keratitis, and myelinated nerve fibers. ^{6 10 21}

The main hormonal abnormality described among patients with KCS is hypocalcemia secondary to hypoparathyroidism, which usually occurs in infancy. ^{5 8 9 11 18} In most recent reports, the treatment for hypocalcemia has been based on the hypoparathyroidism management, which has an adequate response to administration of D vitamin (alfacalcidol) and magnesium (magnesium sulfate/magnesium oxide). ^{3 16} Our patient used calcium carbonate, vitamin D, and calcitriol which corrected hypocalcemia.

KCS1, in addition to being transmitted by an autosomal recessive pattern of inheritance, differs from autosomal dominant KCS2 due to delays in mental development and microcephaly. ^{3 4 6 14} KCS2 patients present a normal intelligence, besides the occurrence, for example, of seizures and cortical calcifications. ^{3 4} In our case, the presence of neuropsychomotor and speech delay, as well as learning disability is remarkable. We do not know if some environmental factor, such as lack of stimulation, could be associated with these findings. This external factor could help to justify her neuropsychomotor delay and learning disability. However, FAM111A is known to be associated with another condition called gracile bone dysplasia (OMIM 615292), which is associated with delayed cognitive development. ²³ Moreover, there are reports in literature associating recurrent seizures and intellectual disability with a delayed diagnosis of hypoparathyroidism. ²⁴ Perhaps a later diagnosis and treatment of hypocalcemia could lead to some degree of intellectual disability.

A better understanding of the possible neurological findings of patients with KCS2 is quite important for management. These individuals usually have long survival and hence understanding of comorbid conditions and their appropriate management may improve quality of life. Moreover, ophthalmologic impairment, secondary to a probable maculopathy, may be a feature of KCS2. After comparing her growth curve with the use of growth hormone, we are not sure if this treatment had some effect, especially because treatment time was short. However, it is noteworthy that the angle of the growth curve during this period seemed to change. Additional studies will be important to define whether eye and neurological findings are part of the disease spectrum of KCS2. Further studies are needed to explore possible benefit from the treatment with GH.

Funding Statement

Funding This work was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).