Kenny - Caffey Syndrome - Types, Risk Factors, Symptoms, Treatment, and Prevention

Introduction

Calcium plays a key role in skeletal mineralization and is required for normal growth, development, and bone strength. Therefore, maintaining equilibrium in calcium levels is necessary to sustain body functions. However, in certain disorders like Kenny-Caffey syndrome, the calcium levels get affected, leading to stunted growth.

What Is Kenny- Caffey Syndrome?

Kenny-Caffey syndrome is a hereditary disorder caused by a mutation in the TBCE (tubulin-folding cofactor E) or FAM111A (family with sequence similarity 111 member A) gene. The symptoms of the disease are growth retardation and the thickening of long bones in the limbs. Other symptoms include

• Low birth weight.

• Bone and skull abnormalities.

• Short stature.

• Hypocalcemia (low calcium level in blood).

What Are the Types of Kenny-Caffey Syndrome?

Kenny-Caffey syndrome is classified into two types

• Type 1 Kenny-Caffey syndrome is an autosomal recessive condition (two copies of the abnormal gene are inherited) with a mutation in the TBCE (tubulin-folding cofactor E) gene. This syndrome is more common in the Middle East.

  • The TBCE gene is responsible for the correct folding of beta tubulins.

  • A mutation in the gene leads to improper folding of tubulin, disrupting the cytoskeletal structure that causes the symptoms associated with type 1 Kenny- Caffey syndrome.

• Type 2 Kenny-Caffey syndrome is an autosomal dominant (one set of the abnormal gene inherited) condition with a mutation in the FAM111A (family with sequence similarity 111 member A) gene. In addition, studies have noted a de novo mutation in the disease without risk factors.

• FAM111A gene causes interaction with proliferating cell nuclear antigen or PCNA (enables DNA replication).

• The mutation leads to impaired DNA replication, causing Type 2 Kenny-Caffey syndrome.

What Are the Risk Factors for Kenny- Caffey Syndrome?

Kenny-Caffey syndrome is a rare condition, and the symptoms of the disease appear in infancy. There is no preference for the disease, affecting all patients equally.

The risk factors associated with the disease are

• A positive family history of the condition.

• Consanguineous parents (parents related by blood, such as first cousins).

• The condition is common in the middle eastern regions due to marriage between close relatives.

What Are the Signs and Symptoms Associated With Kenny- Caffey Syndrome?

The general symptoms include

• Thick outer bones (cortex) with a narrow central cavity (medulla).

• Low blood calcium and high phosphate levels.

• Short stature with small hands and feet.

• Iron deficiency anemia.

• Low serum parathyroid hormone.

• Absence of pores in the skull bone.

• Seizures.

• Deep-set eyes.

• Oral abnormalities include short roots, microdontia, hypodontia, malalignment of teeth, bone loss, difficulty in mastication, dental caries, and tooth agenesis.

Symptoms specific to type 1

• Small head.

• Liver disease in neonates.

• Susceptibility to infections.

• Facial abnormalities include upward slanting of eyes, thin lips, under- developed jaws (micrognathia), flat nasal bridge(giving a 'beak nose' appearance), prominent forehead, and low set ears.

• Low level of neutrophils.

• Abnormal development of teeth and undeveloped nails.

• Mental retardation.

• Growth retardation with delayed milestone development.

• Low weight at birth.

• Corneal cloudiness as a response to inflammation.

Symptoms specific to type 2

• Retinal and corneal calcification.

• Farsightedness (hypermetropia).

• Congenital cataract.

• Abnormally large head (caused by delayed closure of anterior fontanelle) and small eyes.

• Normal mental condition.

• Deficient T-cell immunity.

• Transient hypoparathyroidism and hypomagnesemia.

• Abnormal bone hardening (osteosclerosis).

• Transient hypocalcemia.

What Are the Diagnostic Criteria for Kenny- Caffey Syndrome?

The diagnostic methods include

• Physical assessment by physicians to detect symptoms.

• As the syndrome is hereditary, physicians must take a detailed medical history.

• X-ray is taken to check for skeletal changes. On radiological examination, the features seen are a thickened outer layer of long bones with a narrowing central cavity and the absence of small cavities in the skull.

• Eye examination to detect abnormalities in the eye, such as congenital cataracts and retinal calcification.

• Blood tests detect the body's calcium, magnesium, phosphate, iron, and parathyroid hormone levels.

In Type 1, serum parathyroid hormone was extremely low.

• Molecular genetic testing confirms the diagnosis by checking for TBCE or FAM111A gene. The exome sequencing strategy is used for detection.

What Are the Treatment Options for Kenny -Caffey Syndrome?

Since there is no cure for the syndrome, treatment modalities revolve around symptomatic management.

• Vitamin D and calcium supplements (alfacalcidol) are provided to manage low calcium levels.

• Sodium, levothyroxine, and hydrocortisone to manage hypoparathyroidism during periods of stress.

• Iron supplements are given for anemia.

• Surgery is advised to resolve cataracts.

• Dental procedures are done to repair teeth, and prosthodontic rehabilitation is achieved with tooth-supported telescopic overdenture in case of oligodontia.

• Physiotherapy is done to improve muscle movements.

• Psychological counseling is done as the condition is debilitating.

What Is the Differential Diagnosis of Kenny-Caffey Syndrome?

The differential diagnosis for Type 1 includes

• Kenny-Caffey syndrome two.

• Sanjad- sakati syndrome.

• Di-George syndrome.

• Transient hypoparathyroidism of a diabetic mother.

The differential diagnosis for Type 2 includes

• Type 1 Kenny-Caffey syndrome.

• Osteopetrosis (dense bone prone to fracture).

• Pycnodysostosis (genetic disorder with face and skeletal abnormalities).

• Cleidocranial dysplasia (a genetic disorder affecting teeth and bones).

• Congenital hypoparathyroidism.

What Is the Complication for Kenny–Caffey Syndrome?

• Severe psychomotor retardation with developmental regression.

• Interstitial pulmonary fibrosis.

• Vomiting, diarrhea, and food intolerance.

• GI symptoms like malabsorption and bile-salt-induced diarrhea.

• Pneumonia.

• Liver malfunction.

• Frequent seizures.

• Anemia.

What Is the Prognosis for Kenny-Caffey Syndrome?

As the condition is genetic with no cure, lifelong care is advised. Unfortunately, more than a quarter of patients succumb in early infancy due to severe complications. In addition, quality of life gets affected by bone deformities.

How to Prevent the Development of Kenny-Caffey Syndrome?

There are no guidelines available to prevent the disease. Preimplantation genetic testing of parents and molecular testing of the fetus in the womb can prevent the development of the condition. In case of familial history of the condition, genetic counseling is advised.

Conclusion

Kenny-Caffey syndrome is a debilitating disease causing skeletal anomalies. Due to its rarity, studies are minimal, limiting the scope for effective management and prevention. Therefore, it is important to conduct further research to improve patient quality of life.