Short stature and hypothyroidism in a child with Nail-Patella Syndrome. A case report. / Talla baja e hipotiroidismo en un niño con Síndrome de Nail-Patella. Reporte de un caso clínico.

BACKGROUND: Nail-Patella syndrome (NPS) (OMIM: 161200) or hereditary onycho-osteodysplasia is an autosomal dominant disorder characterized by skeletal anomalies, nail dysplasia, renal and ocular abnor malities. The diagnosis is based on clinical and radiological findings and confirmed by the identification of a heterozygous pathogenic variant in the LMX1B gene. Management of these patients involves conti nuous follow-up and treatment ofthe orthopedical, ocular and renal problems that mayoccur. OBJECTIVE: To describe a case of NPS with short stature and hypothyroidism, an association that has not been described in the literature. CASE REPORT: An eleven-year-old boy with a height of 130 cm (-2.01 Stan dard Deviations [SD]) was referred to the Endocrine Unit at the age of 2 years due to altered thyroid tests. At that time, dysplastic nails and disproportionate short stature were detected. Radiological abnormalities initially suggested a skeletal dysplasia. A primary hypothyroidism was confirmed, without anti-thyroid antibodies and with a normal thyroid ultrasound. Levothyroxine treatment was initiated. The diagnosis of NPS was confirmed by a genetic study with a single pathogenic variant in the LMX1B gene. His father presented a similar phenotype with normal stature. His bone age was equivalent to his chronological age. Laboratory screening for short stature and a GH stimulation test were normal. CONCLUSION: We present a child with proven NPS with short stature and hypothyroi dism. We did not find publications that described this triple association. It can't be ruled out that there could be a relationship between NPS and the thyroid alterations found in this patient.

Talla baja e hipotiroidismo en un niño con Síndrome de Nail-Patella. Reporte de un caso clínico / Short stature and hypothyroidism in a child with Nail-Patella Syndrome. A case report

Resumen: Introducción: El síndrome de Nail-Patella (NPS) es un desorden autosómico dominante caracterizado por anomalías esqueléticas, displasia ungueal, alteraciones renales y oculares. El diagnóstico se sospecha con la clínica y radiología y se confirma por la identificación de una variante patogénica en el gen LMX1B. El manejo de estos pacientes implica un seguimiento continuo y el tratamiento de las posibles complicaciones ortopédicas, oculares y renales. Objetivo: Describir un caso de NPS con talla baja e hipotiroidismo, asociación que no ha sido descrita en la literatura. Caso clínico: Adolescente de 11 años con talla 130 cm (-2,01 Desviaciones Estándar [DE]) fue referido a Endocrinología a los 2 años de edad por pruebas tiroideas alteradas. Se detectaron uñas displásicas y talla baja despro porcionada, además de anormalidades radiológicas sugerentes de displasia esquelética. Se confirmó hipotiroidismo primario, con anticuerpos negativos y ecografía normal, por lo que se inició trata miento con levotiroxina. El diagnóstico de NPS fue confirmado mediante estudio genético de ADN constatándose una variante patogénica en el gen LMX1B. Su padre presentaba un fenotipo similar, con estatura normal. Su edad ósea era acorde con la cronológica. Tanto el estudio general de talla baja como un test de clonidina para estimulación de GH fueron normales. Conclusión: Presentamos un paciente con NPS confirmado, asociado a talla baja e hipotiroidismo. No hallamos publicaciones en la literatura que describieran esta triple asociación. No se descarta que podría haber una relación entre el NPS y las alteraciones tiroideas halladas en este paciente.

Abstract: Background: Nail-Patella syndrome (NPS) (OMIM: 161200) or hereditary onycho-osteodysplasia is an autosomal dominant disorder characterized by skeletal anomalies, nail dysplasia, renal and ocular abnor malities. The diagnosis is based on clinical and radiological findings and confirmed by the identification of a heterozygous pathogenic variant in the LMX1B gene. Management of these patients involves conti nuous follow-up and treatment ofthe orthopedical, ocular and renal problems that mayoccur. Objective: To describe a case of NPS with short stature and hypothyroidism, an association that has not been described in the literature. Case report: An eleven-year-old boy with a height of 130 cm (-2.01 Stan dard Deviations [SD]) was referred to the Endocrine Unit at the age of 2 years due to altered thyroid tests. At that time, dysplastic nails and disproportionate short stature were detected. Radiological abnormalities initially suggested a skeletal dysplasia. A primary hypothyroidism was confirmed, without anti-thyroid antibodies and with a normal thyroid ultrasound. Levothyroxine treatment was initiated. The diagnosis of NPS was confirmed by a genetic study with a single pathogenic variant in the LMX1B gene. His father presented a similar phenotype with normal stature. His bone age was equivalent to his chronological age. Laboratory screening for short stature and a GH stimulation test were normal. Conclusion: We present a child with proven NPS with short stature and hypothyroi dism. We did not find publications that described this triple association. It can't be ruled out that there could be a relationship between NPS and the thyroid alterations found in this patient.

LMX1B-Associated Nephropathy With Type III Collagen Deposition in the Glomerular and Tubular Basement Membranes.

Variants in the LMX1B gene cause nail-patella syndrome, a rare autosomal dominant disorder characterized by dysplasia of nails, patella and elbow abnormalities, iliac "horns," and glaucoma. We describe an adult man with nephrotic syndrome and no systemic manifestations of nail-patella syndrome at the time of his initial kidney biopsy. His kidney biopsy was initially interpreted as a form of segmental sclerosis with unusual fibrillar deposits. At the time of consideration for kidney transplantation, a family history was notable for end-stage renal disease in 3 generations. Subsequent reanalysis of the initial biopsy showed infiltration of the lamina densa by type III collagen fibrils, and molecular studies identified a pathogenic variant in one allele of LMX1B (a guanine to adenine substitution at nucleoide 737 of the coding sequence [c.737G>A], predicted to result in an arginine to glutamine substitution at amino acid 246 [p.Arg246Gln]). This variant has been described previously in multiple unrelated families who presented with autosomal dominant nephropathy without nail and patellar abnormalities.

Steroid-resistant nephrotic syndrome as the initial presentation of nail-patella syndrome: a case of a de novo LMX1B mutation.

BACKGROUND: Nail-patella syndrome (NPS) is an autosomal dominant disorder caused by mutations in the LMX1B gene and is characterized by nail dysplasia, skeletal abnormalities, and nephropathy. We herein report a case of steroid-resistant nephrotic syndrome (SRNS) prior to overt orthopedic symptoms in a patient with NPS. CASE PRESENTATION: A 24-year-old woman presented to our hospital with knee pain. She had poorly developed nails, hypoplastic patellas, dislocation of the elbows, and iliac horns in the pelvis. At the age of 7, she developed nephrotic syndrome and was diagnosed with primary focal segmental glomerulosclerosis by renal biopsy. She received long-term corticosteroid therapy with no obvious response. Her clinical course and orthopedic manifestations indicated NPS, and a genetic analysis showed a de novo mutation in the LMX1B gene (c.819 + 1G > A). Nephropathy in this case was considered to be associated with NPS. Therefore, we discontinued corticosteroids without the exacerbation of nephrotic syndrome. CONCLUSIONS: Patients with NPS may develop nephrotic syndrome prior to overt orthopedic symptoms and only show non-specific findings in renal biopsy at an early stage of NPS nephropathy. Hereditary nephrotic syndrome, often presenting as childhood-onset SRNS, may also be difficult to diagnose in patients with the following conditions: renal symptoms prior to overt extrarenal symptoms, de novo mutations, and non-specific findings in renal biopsy. Therefore, in the management of SRNS in children, we need to reconsider the possibility of hereditary diseases such as NPS even without a family history.

The spectrum of nephrocutaneous diseases and associations: Genetic causes of nephrocutaneous disease.

There are a significant number of diseases and treatment considerations of considerable importance relating to the skin and renal systems. This emphasizes the need for dermatologists in practice or in clinical training to be aware of these associations. Part I of this 2-part continuing medical education article reviews the genetic syndromes with both renal and cutaneous involvement that are most important for the dermatologist to be able to identify, manage, and appropriately refer to nephrology colleagues. Part II reviews the inflammatory syndromes with relevant renal manifestations and therapeutic agents commonly used by dermatologists that have drug-induced effects on or require close consideration of renal function. In addition, we will likewise review therapeutic agents commonly used by nephrologists that have drug-induced effects on the skin that dermatologists are likely to encounter in clinical practice. In both parts of this continuing medical education article, we discuss diagnosis, management, and appropriate referral to our nephrology colleagues in the context of each nephrocutaneous association. There are a significant number of dermatoses associated with renal abnormalities and disease, emphasizing the need for dermatologists to be keenly aware of their presence in order to avoid overlooking important skin conditions with potentially devastating renal complications. This review discusses important nephrocutaneous disease associations with recommendations for the appropriate urgency of referral to nephrology colleagues for diagnosis, surveillance, and early management of potential renal sequelae.

Nail patella syndrome: Knee symptoms and surgical outcomes. A questionnaire-based survey.

BACKGROUND: Patellofemoral instability and dysfunction are frequent symptoms in Nail patella syndrome (NPS). In this article, the first large series of NPS patients is presented in which these knee symptoms were assessed using validated outcome scores. Additionally, the need for surgical interventions, percentage of patients who received surgical treatment and patient reported outcomes are reported. METHODS: A questionnaire based survey was conducted in 139 Dutch NPS patients. Symptoms of the knees were assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS) and Kujala knee score. The questionnaire addressed whether surgical intervention was currently considered, history of past surgeries, type of surgical procedures performed and results of these procedures. RESULTS: Response rate was 74%. Mean KOOS (73.04) and Kujala (74.01) scores showed a wide range and variability between patients. Patellofemoral instability was present in 48.5% of patients. Surgical intervention was currently considered by 12% of patients. Their KOOS and Kujala scores were significantly lower compared to those not considering surgery and they experienced more patellar instability. Surgery was performed on 31 knees in 23 patients. KOOS and Kujala scores were lower in surgically treated versus nonoperated patients but no difference in patellar instability was present. An improvement in pain in 87% and in function in 30% of knees was reported after surgery. Patient satisfaction with the surgical results was 61% and 10% was dissatisfied. Patellar realignment procedures showed similar results, although persistent patellar instability was reported in 40% of patients, not different from nonoperated patients. CONCLUSIONS: Knee symptoms in NPS patients vary widely, with patellar instability present in nearly half of the patients. Although surgical treatment appears unfavourable as surgically treated patients have lower KOOS and Kujala scores, the patient reported surgical results are generally good with a high patient satisfaction. LEVEL OF EVIDENCE: Level IV.

Correction of malformative patellar instability in patients with nail-patella syndrome: a case report and review of the literature.

Nail-patella syndrome (NPS) or hereditary onycho-osteodysplasia is a relatively rare autosomal dominant disorder with the classic tetrad of fingernail abnormalities, hypoplastic patellae, radial head dislocation and iliac horns. The anatomic abnormalities in NPS often lead to subluxation or dislocation of the patellaeca causing knee instability and pain. Although most existing literature regarding the knee manifestation of this syndrome has focused on the clinically and radiological changes, only a few articles discussed the surgical treatment. This study reports the clinical, radiological and arthroscopical findings and a 24-month follow-up after operative stabilisation considering the underlying pathomorphology of malformative patellar instability in an 11-year-old girl. The findings of this study confirm the unique pathology of NPS with a synovial band preventing the engagement of the patella into the trochlear groove. NPS is a rare disorder and has to be considered in cases with untypical patella dislocation. The underlying pathology differs completely from patients with patellofemoral instability. The aim of orthopaedic surgery should be correction of the underlying pathology with resection of the synovial band and an additional realignment of the patella by recentering of the quadriceps muscle. Considering the underlying pathology good clinical results can be expected.

Intercondylar synovial septum in two patients with nail-patella syndrome.

This case report describes the arthroscopic findings in two patients with nail-patella syndrome (NPS). In both cases, a midline synovial septum was encountered that completely subdivided the knee into medial and lateral compartments. One patient required two subsequent arthroscopic procedures, and the synovial septum was found to have recurred even after it had been resected at the initial surgery. The etiology and clinical significance of this anatomic anomaly are unknown, however, surgeons should be aware of its existence and the potential difficulties it may present during knee arthroscopy in patients with NPS.

A case of ectopic cilia in nail-patella syndrome.

Both ectopic cilia and nail-patella syndrome (NPS) are rare entities. To our knowledge we report the first case of the two anomalies coexisting in one patient. We present the case of a 2-year-old girl, with no other ophthalmic complication of NPS, who had an excellent cosmetic outcome and no lesion recurrence following surgical excision of ectopic cilia.

Nail patella syndrome: a rare cause of renal failure in a young adult.

Nail Patella Syndrome (NPS) is a rare hereditary disease affecting multiple systems with predominant involvement of Kidney, Bones and Nails and Eyes. We report a case of NPS which presented as renal failure in a 22 year old male. The patient was admitted with decreased urine output and features of fluid overload and was being evaluated for renal failure. Physical examination revealed associated bony deformities which raised the suspicion of NPS as a possible etiology. This was confirmed by the radiological evaluation which showed the classical features of NPS. Though NPS is a rare clinical condition, physicians should complete knowledge about the components of NPS for appropriate diagnosis and for early detection of other systems involvement.

Nail-patella syndrome and renal involvement. Description of three cases and literature review.

Nail-patella syndrome (NPS) is a rare, autosomal dominant disorder reported in approximatively 1/50,000 individuals. It is characterized by hypoplastic or absent patellae, dystrophic nails, dysplasia of the elbows and iliac horns. Less frequently renal and ocular damages occur. The abnormal gene in NPS is located at the distal end of the long arm of Chromosome 9. Mutations in the human LMX1B gene have been demonstrated to be responsible for NPS. It encodes a LIM-homeodomain transcription factor which plays an important role in limb development in vertebrates. Extensive mutation analysis of different NPS families by different groups failed to demonstrate any genotype-phenotype correlation. Renal involvement occurs in 30-60% of patients and presents with proteinuria and/or microscopic hematuria, edema, hypertension. Progression to nephrotic syndrome occurs in less than 20% of patients, and renal failure in about 10% of NPS patients requiring dialysis and/or transplantation. We report three cases of NPS with different degrees of renal involvement and present a review of the literature on this rare hereditary condition.

How are podocytes affected in nail-patella syndrome?

Nail-patella syndrome is an autosomal-dominant hereditary disease named for dysplastic fingernails and toenails and hypoplastic or absent kneecaps evident in patients with the syndrome. Prognosis is determined by the nephropathy that develops in many such patients. Besides podocyte foot-process effacement, pathognomonic changes in the kidney comprise electron-lucent areas and fibrillar inclusions in the glomerular basement membrane. These characteristic symptoms are caused by mutations in the gene encoding the transcription factor LMX1B, a member of the LIM-homeodomain gene family. Comparable with the human syndrome, homozygous Lmx1b knockout mice lack patellae and suffer from severe podocyte damage. In contrast, however, podocin and the alpha3 and alpha4 chains of collagen IV are absent in the glomeruli of Lmx1b knockout mice. Further studies with podocyte-specific Lmx1b knockout mice have confirmed the importance of LMX1B in podocytes, as these mice apparently develop foot processes initially but lose them later on. We therefore conclude that LMX1B is essential for the development of metanephric precursor cells into podocytes and possibly also for maintaining the differentiation status of podocytes. LMX1B can serve as a model system to elucidate a genetic program in podocytes.

Nail-Patella syndrome: a case report and anesthetic implications.

PURPOSE: To report a case of asystole during combined epidural and general anesthesia occurring in a patient with Nail-Patella syndrome (NPS), and to review the management and anesthetic implications of this rare genetic syndrome. CLINICAL FEATURES: A 64-yr-old male with NPS, renal impairment and coronary artery disease presented for right hemicolectomy for colon cancer. Following initiation of surgery and during insertion of a nasogastric tube there was sudden loss of the patient's pulse oxymetry, and arterial pressure waveforms with an asystolic electrocardiogram signal. Atropine 0.6 mg i.v. was administered and after an asystolic period of 20-30 sec, myocardial activity commenced at 110 beatsxmin(-1) with return of normal vital signs and no further sequelae. CONCLUSIONS: Nail-Patella syndrome can present with an array of anomalies that may be associated with perioperative complications. Glaucoma, nephropathy, vasomotor dysfunction, fragile teeth, abnormal muscle, skeletal and nerve anatomy as well as involvement of the central and/or peripheral nervous systems are common findings. In this setting it is postulated that a vasovagal reflex from esophageal stimulation by nasogastric tube placement may have caused the asystolic event. This response could have been exaggerated by the sympatholytic combination of neuraxial block, preoperative beta-blockade, and potential autonomic dysfunction secondary to NPS. Awareness of this uncommon disease and its presentation may serve to caution the anesthesiologist regarding the perioperative implications of patients with this syndrome.

Nail-patella glomerulopathy without associated constitutional abnormalities.

A 17-year-old boy presented with a history of longstanding hematuria and non-nephrotic proteinuria without renal insufficiency, for which renal biopsy was performed. The findings by routine light microscopy and direct immunofluorescence study were mild and nonspecific. Electron microscopy, however, demonstrated the unexpected finding of distinct collagen fibrils within capillary wall basement membranes, typical of the nail-patella syndrome. Repeat physical examination following the biopsy confirmed the presence of normal nails and patellae, and radiographs of the knees were also normal. The boy's renal disease was stable at last follow-up. The authors briefly discuss the differential diagnosis, and suggest that this case represents an unusual manifestation of the nail-patella syndrome, in which the glomerular changes are present in the absence of the usual associated constitutional abnormalities.

Nail-patella syndrome. Overview on clinical and molecular findings.

Nail-patella syndrome (NPS) is a rare autosomal dominant pleiotropic disorder characterized by dysplasia of the nails, patellar aplasia or hypoplasia, iliac horns, dysplasia of the elbows, and frequently glaucoma and progressive nephropathy. The recent identification of the causative gene for this syndrome has initiated further studies of the phenotype and molecular pathogenesis of kidney disease in NPS. The gene underlying NPS, LMX1B, is a LIM-homeodomain transcription factor involved in normal patterning of the dorsoventral axis of the limb during development and early morphogenesis of the glomerular basement membrane. Molecular studies of Lmx1b, combined with genetic and immunohistochemical investigation of different alpha chains of type IV collagen in the Lmx1b null mice kidney, a mouse model for NPS, have provided evidence that Lmx1b is involved in the pathogenesis of NPS glomerulopathy. At present evidence for a correlation between the presence and severity of the renal and extrarenal anomalies and LMX1B genotype is lacking. This review focuses on the recent advances in clinical and molecular genetic studies of NPS.