Nail-Patella Syndrome

NPS is either present at birth or in early childhood. The features of the disease vary from one person to another. 

Nails

Nail changes are observed in most patients and are usually bilateral [5]. The most commonly involved fingernails are on the first, third, and fifth digits. Furthermore, the thumbnail deformity is more prominent than the others. Specifically, the nails are characteristically small, narrow, thin or thick, ridged, split and possibly discolored. Most cases feature a malformed lunula with a characteristic triangle shape. In contrast to fingernails, the toenails are less affected.

Bones

A majority of patients with NPS exhibit bone abnormalities in the patella. Specifically, one or both patellas are either absent, abnormally small, hypoplastic, or shaped incorrectly [8]. Additionally, the patella may be displaced laterally and superiorly. Knee manifestations are seen in 74% of affected patients according to one study [5].

Other lower extremity bones may also have deformities. Hypoplasia of the fibula and femur causes subluxation or partial dislocation of the knee, which contribute to the restriction of movement. Moreover, patients exhibit genu varum, or "bow-leg" of the affected leg(s). This condition may result in complications such as progressive bone degeneration, knee pain, stiffness, and osteoarthritis.

Elbow involvement is also common in patients with NPS [5]. The deformities are seen in the head of the radius and capitellum of the humerus, of which either can be small and hypoplastic. Some also have webbing of the skin at the antecubital region of the elbow. These patients exhibit a limited range of movement in arm extension, pronation, or supination as well as subluxation. 

In affected hipbones, abnormal projections arise from the superior portions of the bilateral iliac horns. In fact, this is pathognomonic of the disease [5] and can be seen on fetal ultrasound [9]. It is can also be observed on X-rays in affected babies and children. Other skeletal features are scapular hypoplasia, scoliosis, and pectus excavatum [5].

Eyes

Glaucoma is a potentially serious clinical manifestation that occurs secondary to fluid blockage. With increasing fluid pressure, patients may experience headaches, blurry vision, and other visual problems. This condition may progress to loss of peripheral vision and blindness. Other eye abnormalities include the hyperpigmentation of the pupillary margin of the eye called Lester’s sign [5]. In addition, cataracts and microcornea could develop.

Kidneys

Nephropathy, which may present in childhood or later stages, is demonstrated in approximately 30% to 40% of patients. This manifestation is attributed to the degeneration of renal tubules and/or glomeruli. Hence, nephrotic and/or glomerular disease develop.

The first clinical signs of nephropathy are hematuria, hypertension, and possibly edema. While kidney disease could be benign, it has the potential to progress to renal failure. In those with nephropathy, they may develop nephrotic syndrome. Some progress to kidney failure but this is less likely to occur before the fourth decade of life.

Other

There are neurologic symptoms in NPS such as numbness, tingling, and burning sensations represented in a glove and stocking pattern. Furthermore, epilepsy has been reported in a small percentage of patients [5]. Vasomotor symptoms due to poor circulation such as Raynaud’s phenomenon may be present. Also, patients can experience gastrointestinal problems such as constipation and irritable bowel syndrome. Often the former is seen in infancy [5]. Finally, dental issues may arise resulting in weak teeth and thin enamel. The overall general appearance of these individuals is depicted by lean body with little muscle. These patients may have curved spines.

The workup includes a thorough physical exam, detailed patient and family history, imaging, and laboratory testing [8]. Fetal ultrasound can detect NPS prenatally with findings suggestive of characteristic limb abnormalities.

Imaging modalities can be utilized. Radiographs, CT, and/or MRI are used to identify bone abnormalities characteristic of NPS such as those found in the patella, radial head or ilium.

Laboratory studies include urinalysis which reveals hematuria and proteinuria. Serum albumin measurement is important in nephrotic patients, in which hypoalbuminemia is demonstrated. Additionally, a complete blood count will detect anemia if present. A combination of anemia, edema, and hypoalbuminemia is highly suspicious of nephrotic syndrome. 

A renal biopsy will display structural abnormalities that may be present even in asymptomatic patients [10]. Histologically, the findings include capillary wall thickening, collagen deposition, and focal and segmental sclerosis.

Treatment of NPS consists of symptomatic and supportive measures. Patients with nephropathy are treated with ACE inhibitors for proteinuria. Also, a nephrology consult is indicated in these cases. Patients with open-angle glaucoma are treated the same as the general population. 

In some cases, physical therapy and other early orthopedic interventions are indicated such as knee replacement surgery and/or knee reconstruction. Also, elbow reconstruction surgery may be appropriate. Moreover, management of scoliosis may involve braces, casts or surgery.

Genetic counseling is beneficial in providing information and education for the patient and family members. Genetic screening may be offered, too. Clinicians should consider examination of family members.

NPS patients should undergo surveillance tests to monitor the progression of the disease. Yearly exams include [5]:

• Blood pressure screening
• Screening for renal dysfunction through urinalysis, urine protein/creatinine ratio, and albumin/creatinine ratio
• Screening for presence of glaucoma, cataracts, and microcornea through optic exam

Further management includes monitoring scoliosis in children and adolescents. Caution with NSAIDS, longterm use may have damaging renal effects.

Patients with NPS generally lead ordinary lives but will need close monitoring and surveillance. Those with nephropathy that progresses to end-stage renal disease may require a transplant. Consequently, they do well afterwards.

The etiology of NPS is due to mutations in LMX1B gene, which is a homeobox transcription factor that plays a significant role in the development of limbs, kidneys, and eyes. Specifically, this gene controls the dorsal-ventral pattern of embryological development [3] [4]. Approximately 80% of those with NPS inherited it from an affected parent. One study showed that 87.5% of NPS patients inherited the disorder while the remainder were sporadic. [5]. 

The incidence of NPS is 22 per 1,000,000 population [6]. There is no gender preference in NPS. Abnormalities of nails, knees, and elbows are usually found at birth. However, patellar deformities are noted in childhood while renal manifestations can develop at any age. Also, glaucoma usually develops in adulthood.

NPS occurs as a result of a mutated transcription factor. Various bones are affected such as the patella, ilium, radius, and humerus. Additionally, the nails are affected. Severe features include nephropathy and glaucoma [7]. Approximately 30% to 55% develop nephropathy [5] and about 5% of those with nephropathy progress to end-stage renal failure. It is thought that pathogenic variants of the LMX1B genes may be linked to proteinuria. 

This disease cannot be avoided since it is genetic. However, renal problems and eye abnormalities such as glaucoma could be prevented with close surveillance. Hence, it is paramount for the patient to maintain close follow up with the medical team. Individuals with NPS and their family members may undergo genetic counseling and testing to learn about their chances of inheriting the disease and what NPS entails for future offspring.

Nail-Patella Syndrome (NPS), an autosomal dominant disorder, is characterized by a gene mutation in the transcription factor LMX1B, which results in deformity of nails and bones. Specifically, NPS affects bones in the knees, hips, and elbows. While some presentations are mild and benign, the sequelae vary from one individual to another [1] [2]. Complications include nephropathy and glaucoma.

Diagnosis is achieved through a comprehensive history and physical. Furthermore, it is pertinent to test for any renal or ocular disease through appropriate studies. Early identification of abnormalities results in more prompt treatment and delay of progression. Therefore, surveillance such as annual blood pressure measurement and studies assessing for proteinuria are highly recommended.

Therapy depends on the clinical picture. For individuals with bone deformities, physical therapy and surgical interventions may be indicated. Also, patients with nephropathy or glaucoma will be treated with appropriate medications. Most people commonly lead normal lives but should adhere to close follow up appointments with the medical team.

Nail-Patella Syndrome (NPS) is a disorder due to a mutated gene called LMX1B, which is involved in developing the limbs. NPS is an autosomally dominant disease. This means that one of the parents has a copy of the mutated gene and copy of the good gene. Therefore, there is a 50% chance of passing it to a child. 

This disease affects nails, bones and may even cause problems with kidneys and eyes. Usually, the presentation is at birth. Other cases present in childhood or later. Some individuals will have mild symptoms and signs while others may have more serious ones. The features are:

Nails

• Nails are usually small, ridged, split, thickened, discolored or may be completely absent. 
• Abnormal nails are most commonly found on the thumbs, index, and middle fingers. 

Bones

• One or both patellas (kneecaps) may be abnormal, they could be too small or irregularly shaped.
• Patella may be dislocated and deformed or even absent in one or both legs. The legs may even be bow legged.
• There is knee pain, instability, and possibly limited movement.
• In affected elbows, there is the inability to extend the arm and the elbow may angle outwards.

Kidney                                                      

• Some patients will have protein in their urine without any clinical symptoms. In a small percentage of patients, this may progress to serious problems such as kidney failure although it is rare. 

Eye

• Some patients have glaucoma, which is increased pressure in the eye. Cataracts and other abnormalities may also occur.

Neurological

• Numbness and tingling in hands and feet may be present.

Gastrointestinal

• Commonly found symptoms are irritable bowel syndrome (IBS) or constipation.

Circulation

• Some patiemts will feel cold hand and feet due to inadequate blood supply.

Diagnosis depends on a thorough medical history of the patient and the patient’s family members as well as a detailed exam of the patient. Certain signs of NPS such as hip bone abnormalities can be seen on prenatal ultrasound. Also, X-rays or other imaging can detect abnormalities.

Early intervention to provide support and physical therapy is also impotant. In addition, the patient will have regular follow up appointments. The doctor will monitor blood pressure and perform urine tests to check for protein. Children and adolescents are checked for scoliosis. Also recommended are dental exams twice a year and eye exams to check for glaucoma, cataracts, and other eye problems. Treatment is reserved for signs and symptoms. 

Genetic counseling for the affected individual and family is available and usually beneficial. This involves assessment and discussion of passing on the disorder to future offspring. Parents can make informed decisions under the guidance of a medical professional. Genetic testing may be offered as well. Overall patients live normal lives, but close follow up is the key. 

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